HIV replication inhibiting pyrimidines

ABSTRACT

This invention concerns HIV replication inhibitors of formula 
                         
the N-oxides, the pharmaceutically acceptable addition salts, the quaternary amines and the stereochemically isomeric forms thereof, wherein the ring containing -a 1 =a 2 -a 3 =a 4 - and -b 1 =b 2 -b 3 =b 4 - represents phenyl, pyridyl, pyrimidinyl, pirazinyl, pyridazinyl; n is 0 to 5; m is 1 to 4; R 1  is hydrogen; aryl; formyl; C 1-6 alkylcarbonyl; C 1-6 alkyl; C 1-6 alkyloxycarbonyl; substituted C 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkyloxycarbonyl, C 1-6 alkylcarbonyloxy; substituted C 1-6 alkyloxyC 1-6 alkylcarbonyl; R 2  is hydroxy, halo, optionally substituted C 1-6 alkyl, C 3-7 cycloalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 1-6 alkyloxy, C 1-6 alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono- or di(C 1-6 alkyl)amino, polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, —S(═O) p R 6 , —NH—S(═O) p R 6 , —C(═O)R 6 , —NHC(═O)H, —C(═O)NHNH 2 , —NHC(═O)R 6 , —C(═NH)R 6  or a 5-membered heterocycle; X 1  is —NR 5 —, —NH—NH—, —N═N—, —O—, —C(═O)—, C 1-4 alkanediyl, —CHOH—, —S—, —S(═O) p —, —X 2 —C 1-4 alkanediyl- or —C 1-4 alkanediyl-X 2 —; R 3  is NHR 13 ; NR 13 R 14 ; —C(═O)—NHR 13 ; —C(═O)—NR 13 R 14 ; —C(═O)—R 15 ; —CH═N—NH—C(═O)—R 16 ; substituted C 1-6 alkyl; optionally substituted C 1-6 alkyloxyC 1-6 alkyl; substituted C 2-6 alkenyl; substituted C 2-6 alkynyl; C 1-6 alkyl substituted with hydroxy and a second substituent; —C(═N—O—R 8 )—C 1-4 alkyl; R 7 ; or —X 3 —R 7 ; R 4  is halo, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkyloxy, cyano, nitro, polyhaloC 1-6 alkyl, polyhaloC 1-6 alkyloxy, aminocarbonyl, C 1-6 alkyloxycarbonyl, C 1-6 alkylcarbonyl, formyl, amino, mono- or di(C 1-4 alkyl)amino; their use as a medicine, their processes for preparation and pharmaceutical compositions comprising them.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a divisional of U.S. application Ser. No. 13/249796, filed 30Sep. 2011, which is a continuation of Ser. No. 11/474,855, filed Jun.26, 2006, which is a continuation of U.S. application Ser. No.10/485,636, filed Feb. 3, 2004, now U.S. Pat. No. 7,125,879, which is anational stage of PCT Application No. PCT/EP2002/008953, filed Aug. 9,2002, which claims priority for EPO Patent Application No. 01203090.4,filed Aug. 13, 2001 and EPO Patent Application No. 02077748.8, filedJun. 10, 2002, all of which are hereby incorporated by reference intheir entirety.

The present invention is concerned with pyrimidine derivatives havingHIV (Human Immunodeficiency Virus) replication inhibiting properties.The invention further relates to methods for their preparation andpharmaceutical compositions comprising them. The invention also relatesto the use of said compounds for the manufacture of a medicament for theprevention or the treatment of HIV infection.

Compounds structurally related to the present compounds are disclosed inthe prior art.

WO 99/50250 and WO 00/27825 disclose substituted aminopyrimidines havingHIV replication inhibiting properties.

WO 97/19065 discloses substituted 2-anilinopyrimidines useful as proteinkinase inhibitors.

WO 00/62778 concerns cyclic protein tyrosine kinase inhibitors.

WO 98/41512 describes substituted 2-anilinopyrimidines useful as proteinkinase inhibitors.

U.S. Pat. No. 5,691,364 describes benzamidine derivatives and their useas anti-coagulants.

WO 00/78731 describes 5-cyano-2-aminopyrimidine derivatives as KDRkinase or FGFr kinase inhibitors useful in the prophylaxis and treatmentof diseases associated with angiogenesis.

The compounds of the invention differ from the prior art compounds instructure, pharmacological activity and/or pharmacological potency.

Unexpectedly, it has been found that the compounds of the invention havean improved ability to inhibit the replication of Human ImmunodeficiencyVirus (HIV), in particular they have an improved ability to inhibit thereplication of mutant strains, i.e. strains which have become resistantto art-known drug(s) (drug or multidrug resistant HIV strains).

The present invention concerns a compound of formula

a N-oxide, a pharmaceutically acceptable addition salt, a quaternaryamine or a stereochemically isomeric form thereof, wherein

-   -a¹=a²-a³=a⁴- represents a bivalent radical of formula    —CH═CH—CH═CH—  (a-1);    —N═CH—CH═CH—  (a-2);    —N═CH—N═CH—  (a-3);    —N═CH—CH═N—  (a-4);    —N═N—CH═CH—  (a-5);-   -b¹=b²-b³=b⁴- represents a bivalent radical of formula    —CH═CH—CH═CH—  (b-1);    —N═CH—CH═CH—  (b-2);    —N═CH—N═CH—  (b-3);    —N═CH—CH═N—  (b-4);    —N═N—CH═CH—  (b-5);-   n is 0, 1, 2, 3 or 4; and in case -a¹=a²-a³=a⁴- is (a-1), then n may    also be 5;-   m is 1, 2, 3 and in case -b¹=b²-b³=b⁴- is (b-1), then m may also be    4;-   R¹ is hydrogen; aryl; formyl; C₁₋₆alkylcarbonyl; C₁₋₆alkyl;    C₁₋₆alkyloxycarbonyl; C₁₋₆alkyl substituted with formyl,    C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonyloxy;    C₁₋₆alkyloxyC₁₋₆alkylcarbonyl substituted with C₁₋₆alkyloxycarbonyl;-   each R² independently is hydroxy, halo, C₁₋₆alkyl optionally    substituted with cyano or —C(═O)R⁶, C₃₋₇cycloalkyl, C₂₋₆alkenyl    optionally substituted with one or more halogen atoms or cyano,    C₂₋₆alkynyl optionally substituted with one or more halogen atoms or    cyano, C₁₋₆alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono- or    di(C₁₋₆alkyl)amino, polyhalomethyl, polyhalomethylthio,    —S(═O)_(p)R⁶, —NH—S(═O)_(p)R⁶, —C(═O)R⁶, —NHC(═O)H, —C(═O)NHNH₂,    —NHC(═O)R⁶, —C(═NH)R⁶ or a radical of formula

-   -   wherein each A₁ independently is N, CH or CR^(O); and        -   A₂ is NH, O, S or NR⁶;

-   X₁ is —NR⁵—, —NH—NH—, —N═N—, —O—, —C(═O)—, C₁₋₄alkanediyl, —CHOH—,    —S—, —S(═O)_(p)—, —X₂—C₁₋₄alkanediyl- or —C₁₋₄alkanediyl-X₂—;

-   X₂ is —NR⁵—, —NH—NH—, —N═N—, —O—, —C(═O)—, —CHOH—, —S—, —S(═O)_(p)—;

-   R³ is NHR¹³; NR¹³R¹⁴; —C(═O)—NHR¹³; —C(═O)—NR¹³R¹⁴; —C(═O)—R¹⁵;    —CH═N—NH—C(═O)—R¹⁶; C₁₋₆alkyl substituted with one or more    substituents each independently selected from cyano, NR⁹R¹⁰,    —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl or R⁷; C₁₋₆alkyl substituted with    one or more substituents each independently selected from cyano,    NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl or R⁷ and wherein 2 hydrogen    atoms bound at the same carbon atom are replaced by C₁₋₄alkanediyl;    C₁₋₆alkyl substituted with hydroxy and a second substituent selected    from cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl or R⁷;    C₁₋₆alkyloxyC₁₋₆alkyl optionally substituted with one or more    substituents each independently selected from cyano, NR⁹R¹⁰,    —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl or R⁷; C₂₋₆alkenyl substituted with    one or more substituents each independently selected from halo,    cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl or R⁷; C₂₋₆alkynyl    substituted with one or more substituents each independently    selected from halo, cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl    or R⁷; —C(═N—O—R⁸)—C₁₋₄alkyl; R⁷ or —X₃—R⁷;

-   X₃ is —NR⁵—, —NH—NH—, —N═N—, —O—, —C(═O)—, —S—, —S(═O)_(p)—,    —X₂—C₁₋₄alkanediyl-, —C₁₋₄alkanediyl-X_(2a)—,    —C₁₋₄alkanediyl-X_(2b)—C₁₋₄alkanediyl, —C(═N—OR⁸)—C₁₋₄alkanediyl-;    -   with X_(2a) being —NH—NH—, —N═N—, —O—, —C(═O)—, —S—,        —S(═O)_(p)—; and    -   with X_(2b) being —NH—NH—, —N═N—, —C(═O)—, —S—, —S(═O)_(p)—;

-   R⁴ is halo, hydroxy, C₁₋₆alkyl, C₃₋₇cycloalkyl, C₁₋₆alkyloxy, cyano,    nitro, polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy, aminocarbonyl,    C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonyl, formyl, amino, mono- or    di(C₁₋₄alkyl)amino or R⁷;

-   R⁵ is hydrogen; aryl; formyl; C₁₋₆alkylcarbonyl; C₁₋₆alkyl;    C₁₋₆alkyloxycarbonyl; C₁₋₆alkyl substituted with formyl,    C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl or C₁₋₆alkylcarbonyloxy;    C₁₋₆alkyloxyC₁₋₆alkylcarbonyl substituted with C₁₋₆alkyloxycarbonyl;

-   R⁶ is C₁₋₄alkyl, amino, mono- or di(C₁₋₄alkyl)amino or    polyhaloC₁₋₄alkyl;

-   R⁷ is a monocyclic, bicyclic or tricyclic saturated, partially    saturated or aromatic carbocycle or a monocyclic, bicyclic or    tricyclic saturated, partially saturated or aromatic heterocycle,    wherein each of said carbocyclic or heterocyclic ring systems may    optionally be substituted with one, two, three, four or five    substituents each independently selected from halo, hydroxy,    mercapto, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl, mono or    di(C₁₋₆alkyl)aminoC₁₋₆alkyl, formyl, C₁₋₆alkylcarbonyl,    C₃₋₇cycloalkyl, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylthio,    cyano, nitro, polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy,    aminocarbonyl, —CH(═N—O—R⁸), R^(7a), —X₃—R^(7a) or R^(7a)—C₁₋₄alkyl;

-   R^(7a) is a monocyclic, bicyclic or tricyclic saturated, partially    saturated or aromatic carbocycle or a monocyclic, bicyclic or    tricyclic saturated, partially saturated or aromatic heterocycle,    wherein each of said carbocyclic or heterocyclic ring systems may    optionally be substituted with one, two, three, four or five    substituents each independently selected from halo, hydroxy,    mercapto, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl, mono or    di(C₁₋₆alkyl)aminoC₁₋₆alkyl, formyl, C₁₋₆alkylcarbonyl,    C₃₋₇cycloalkyl, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylthio,    cyano, nitro, polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy,    aminocarbonyl, —CH(═N—O—R⁸);

-   R⁸ is hydrogen, C₁₋₄alkyl, aryl or arylC₁₋₄alkyl;

-   R⁹ and R¹⁰ each independently are hydrogen; hydroxy; C₁₋₆alkyl;    C₁₋₆alkyloxy; C₁₋₆alkylcarbonyl; C₁₋₆alkyloxycarbonyl; amino; mono-    or di(C₁₋₆alkyl)amino; mono- or di(C₁₋₆alkyl)aminocarbonyl;    —CH(═NR¹¹) or R⁷, wherein each of the aforementioned C₁₋₆alkyl    groups may optionally and each individually be substituted with one    or two substituents each independently selected from hydroxy,    C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy, carboxyl, C₁₋₆alkyloxycarbonyl,    cyano, amino, imino, mono- or di(C₁₋₄alkyl)amino, polyhalomethyl,    polyhalomethyloxy, polyhalomethylthio, —S(═O)_(p)R⁶,    —NH—S(═O)_(p)R⁶, —C(═O)R⁶, —NHC(═O)H, —C(═O)NHNH₂, —NHC(═O)R⁶,    —C(═NH)R⁶, R⁷; or

-   R⁹ and R¹⁰ may be taken together to form a bivalent or trivalent    radical of formula    —CH₂—CH₂—CH₂—CH₂—  (d-1)    —CH₂—CH₂—CH₂—CH₂—CH₂—  (d-2)    —CH₂—CH₂—O—CH₂—CH₂—  (d-3)    —CH₂—CH₂—S—CH₂—CH₂—  (d-4)    —CH₂—CH₂—NR¹²—CH₂—CH₂—  (d-5)    —CH₂—CH═CH—CH₂—  (d-6)    ═CH—CH═CH—CH═CH—  (d-7)

-   R¹¹ is cyano; C₁₋₄alkyl optionally substituted with C₁₋₄alkyloxy,    cyano, amino, mono- or di(C₁₋₄alkyl)amino or aminocarbonyl;    C₁₋₄alkylcarbonyl; C₁₋₄alkyloxycarbonyl; aminocarbonyl; mono- or    di(C₁₋₄alkyl)aminocarbonyl;

-   R¹² is hydrogen or C₁₋₄alkyl;

-   R¹³ and R¹⁴ each independently are C₁₋₆alkyl optionally substituted    with cyano or aminocarbonyl, C₂₋₆alkenyl optionally substituted with    cyano or aminocarbonyl, C₂₋₆alkynyl optionally substituted with    cyano or aminocarbonyl;

-   R¹⁵ is C₁₋₆alkyl substituted with cyano or aminocarbonyl;

-   R¹⁶ is C₁₋₆alkyl optionally substituted with cyano or aminocarbonyl,    or R⁷;

-   p is 1 or 2;

-   aryl is phenyl or phenyl substituted with one, two, three, four or    five substituents each independently selected from halo, hydroxy,    mercapto, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl, mono or    di(C₁₋₆alkyl)aminoC₁₋₆alkyl, C₁₋₆alkylcarbonyl, C₃₋₇cycloalkyl,    C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylthio, cyano, nitro,    polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy, aminocarbonyl, R⁷ or    —X₃—R⁷.

As used hereinbefore or hereinafter C₁₋₄alkyl as a group or part of agroup defines straight or branched chain saturated hydrocarbon radicalshaving from 1 to 4 carbon atoms such as methyl, ethyl, propyl,1-methylethyl, butyl; C₁₋₆alkyl as a group or part of a group definesstraight or branched chain saturated hydrocarbon radicals having from 1to 6 carbon atoms such as the group defined for C₁₋₄alkyl and pentyl,hexyl, 2-methylbutyl and the like; C₂₋₆alkyl as a group or part of agroup defines straight or branched chain saturated hydrocarbon radicalshaving from 2 to 6 carbon atoms such as ethyl, propyl, 1-methylethyl,butyl, pentyl, hexyl, 2-methylbutyl and the like; C₁₋₄alkanediyl definesstraight or branched chain saturated bivalent hydrocarbon radicalshaving from 1 to 4 carbon atoms such as methylene, 1,2-ethanediyl or1,2-ethylidene, 1,3-propanediyl or 1,3-propylidene, 1,4-butanediyl or1,4-butylidene and the like; C₃₋₇cycloalkyl is generic to cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; C₂₋₆alkenyl definesstraight and branched chain hydrocarbon radicals having from 2 to 6carbon atoms containing a double bond such as ethenyl, propenyl,butenyl, pentenyl, hexenyl and the like; C₂₋₆alkynyl defines straightand branched chain hydrocarbon radicals having from 2 to 6 carbon atomscontaining a triple bond such as ethynyl, propynyl, butynyl, pentynyl,hexynyl and the like; a monocyclic, bicyclic or tricyclic saturatedcarbocycle represents a ring system consisting of 1, 2 or 3 rings, saidring system being composed of only carbon atoms and said ring systemcontaining only single bonds; a monocyclic, bicyclic or tricyclicpartially saturated carbocycle represents a ring system consisting of 1,2 or 3 rings, said ring system being composed of only carbon atoms andcomprising at least one double bond provided that the ring system is notan aromatic ring system; a monocyclic, bicyclic or tricyclic aromaticcarbocycle represents an aromatic ring system consisting of 1, 2 or 3rings, said ring system being composed of only carbon atoms; the termaromatic is well known to a person skilled in the art and designatescyclically conjugated systems of 4n+2 electrons, that is with 6, 10, 14etc. π-electrons (rule of Hückel); a monocyclic, bicyclic or tricyclicsaturated heterocycle represents a ring system consisting of 1, 2 or 3rings and comprising at least one heteroatom selected from O, N or S,said ring system containing only single bonds; a monocyclic, bicyclic ortricyclic partially saturated heterocycle represents a ring systemconsisting of 1, 2 or 3 rings and comprising at least one heteroatomselected from O, N or S, and at least one double bond provided that thering system is not an aromatic ring system; a monocyclic, bicyclic ortricyclic aromatic heterocycle represents an aromatic ring systemconsisting of 1, 2 or 3 rings and comprising at least one heteroatomselected from O, N or S.

Particular examples of monocyclic, bicyclic or tricyclic saturatedcarbocycles are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, bicyclo[4,2,0]octanyl, cyclononanyl,cyclodecanyl, decahydronapthalenyl, tetradecahydroanthracenyl and thelike.

Particular examples of monocyclic, bicyclic or tricyclic partiallysaturated carbocycles are cyclopropenyl, cyclobutenyl, cyclopentenyl,cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclo[4,2,0]octenyl,cyclononenyl, cyclodecenyl, octahydronaphthalenyl,1,2,3,4-tetrahydronaphthalenyl, 1,2,3,4,4a,9,9a,10-octahydro-anthracenyland the like.

Particular examples of monocyclic, bicyclic or tricyclic aromaticcarbocycles are phenyl, naphthalenyl, anthracenyl.

Particular examples of monocyclic, bicyclic or tricyclic saturatedheterocycles are tetrahydrofuranyl, pyrrolidinyl, dioxolanyl,imidazolidinyl, thiazolidinyl, tetrahydrothienyl, dihydrooxazolyl,isothiazolidinyl, isoxazolidinyl, oxadiazolidinyl, triazolidinyl,thiadiazolidinyl, pyrazolidinyl, piperidinyl, hexahydropyrimidinyl,hexahydropyrazinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl,piperazinyl, trithianyl, decahydroquinolinyl, octahydroindolyl and thelike.

Particular examples of monocyclic, bicyclic or tricyclic partiallysaturated heterocycles are pyrrolinyl, imidazolinyl, pyrazolinyl,2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl,2,3-dihydro-1,4-benzodioxinyl, indolinyl and the like.

Particular examples of monocyclic, bicyclic or tricyclic aromaticheterocycles are azetyl, oxetylidenyl, pyrrolyl, furyl, thienyl,imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl,triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidinyl,pyrazinyl, pyridazinyl, triazinyl, pyranyl, benzofuryl, isobenzofuryl,benzothienyl, isobenzothienyl, indolizinyl, indolyl, isoindolyl,benzoxazolyl, benzimidazolyl, indazolyl, benzisoxazolyl,benzisothiazolyl, benzopyrazolyl, benzoxadiazolyl, benzothiadiazolyl,benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl,quinolizinyl, phthalazinyl, quinoxalinyl, quinazolinyl, naphthiridinyl,pteridinyl, benzopyranyl, pyrrolopyridyl, thienopyridyl, furopyridyl,isothiazolopyridyl, thiazolopyridyl, isoxazolopyridyl, oxazolopyridyl,pyrazolopyridyl, imidazopyridyl, pyrrolopyrazinyl, thienopyrazinyl,furopyrazinyl, isothiazolopyrazinyl, thiazolopyrazinyl,isoxazolopyrazinyl, oxazolopyrazinyl, pyrazolopyrazinyl,imidazopyrazinyl, pyrrolopyrimidinyl, thienopyrimidinyl,furopyrimidinyl, isothiazolopyrimidinyl, thiazolopyrimidinyl,isoxazolopyrimidinyl, oxazolopyrimidinyl, pyrazolopyrimidinyl,imidazopyrimidinyl, pyrrolopyridazinyl, thienopyridazinyl,furopyridazinyl, isothiazolopyridazinyl, thiazolopyridazinyl,isoxazolopyridazinyl, oxazolopyridazinyl, pyrazolopyridazinyl,imidazopyridazinyl, oxadiazolopyridyl, thiadiazolopyridyl,triazolopyridyl, oxadiazolopyrazinyl, thiadiazolopyrazinyl,triazolopyrazinyl, oxadiazolopyrimidinyl, thiadiazolopyrimidinyl,triazolopyrimidinyl, oxadiazolopyridazinyl, thiadiazolopyridazinyl,triazolopyridazinyl, imidazooxazolyl, imidazothiazolyl,imidazoimidazolyl, isoxazolotriazinyl, isothiazolotriazinyl,pyrazolotriazinyl, oxazolotriazinyl, thiazolotriazinyl,imidazotriazinyl, oxadiazolotriazinyl, thiadiazolotriazinyl,triazolotriazinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl,phenoxazinyl and the like.

As used herein before, the term (═O) forms a carbonyl moiety whenattached to a carbon atom, a sulfoxide moiety when attached to a sulfuratom and a sulfonyl moiety when two of said terms are attached to asulfur atom.

The term halo is generic to fluoro, chloro, bromo and iodo. As used inthe foregoing and hereinafter, polyhalomethyl as a group or part of agroup is defined as mono- or polyhalosubstituted methyl, in particularmethyl with one or more fluoro atoms, for example, difluoromethyl ortrifluoromethyl; polyhaloC₁₋₄alkyl or polyhaloC₁₋₆alkyl as a group orpart of a group is defined as mono- or polyhalosubstituted C₁₋₄alkyl orC₁₋₆alkyl, for example, the groups defined in halomethyl,1,1-difluoro-ethyl and the like. In case more than one halogen atoms areattached to an alkyl group within the definition of polyhalomethyl,polyhaloC₁₋₄alkyl or polyhaloC₁₋₆alkyl, they may be the same ordifferent.

The term heterocycle in the definition of R⁷ or R^(7a) is meant toinclude all the possible isomeric forms of the heterocycles, forinstance, pyrrolyl comprises 1H-pyrrolyl and 2H-pyrrolyl.

The carbocycle or heterocycle in the definition of R⁷ or R^(7a) may beattached to the remainder of the molecule of formula (I) through anyring carbon or heteroatom as appropriate, if not otherwise specified.Thus, for example, when the heterocycle is imidazolyl, it may be1-imidazolyl, 2-imidazolyl, 4-imidazolyl and the like, or when thecarbocycle is naphthalenyl, it may be 1-naphthalenyl, 2-naphthalenyl andthe like.

When any variable (eg. R⁷, X₂) occurs more than one time in anyconstituent, each definition is independent.

Lines drawn from substituents into ring systems indicate that the bondmay be attached to any of the suitable ring atoms.

For therapeutic use, salts of the compounds of formula (I) are thosewherein the counterion is pharmaceutically acceptable. However, salts ofacids and bases which are non-pharmaceutically acceptable may also finduse, for example, in the preparation or purification of apharmaceutically acceptable compound. All salts, whetherpharmaceutically acceptable or not are included within the ambit of thepresent invention.

The pharmaceutically acceptable addition salts as mentioned hereinaboveare meant to comprise the therapeutically active non-toxic acid additionsalt forms which the compounds of formula (I) are able to form. Thelatter can conveniently be obtained by treating the base form with suchappropriate acids as inorganic acids, for example, hydrohalic acids,e.g. hydrochloric, hydrobromic and the like; sulfuric acid; nitric acid;phosphoric acid and the like; or organic acids, for example, acetic,propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, oxalic,malonic, succinic, maleic, fumaric, malic, tartaric,2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic,benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic,2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids.Conversely the salt form can be converted by treatment with alkali intothe free base form.

The compounds of formula (I) containing acidic protons may be convertedinto their therapeutically active non-toxic metal or amine addition saltforms by treatment with appropriate organic and inorganic bases.Appropriate base salt forms comprise, for example, the ammonium salts,the alkali and earth alkaline metal salts, e.g. the lithium, sodium,potassium, magnesium, calcium salts and the like, salts with organicbases, e.g. primary, secondary and tertiary aliphatic and aromaticamines such as methylamine, ethylamine, propylamine, isopropylamine, thefour butylamine isomers, dimethylamine, diethylamine, diethanolamine,dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine,piperidine, morpholine, trimethylamine, triethylamine, tripropylamine,quinuclidine, pyridine, quinoline and isoquinoline, the benzathine,N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3-propanediol,hydrabamine salts, and salts with amino acids such as, for example,arginine, lysine and the like. Conversely the salt form can be convertedby treatment with acid into the free acid form.

The term addition salt also comprises the hydrates and solvent additionforms which the compounds of formula (I) are able to form. Examples ofsuch forms are e.g. hydrates, alcoholates and the like.

The term “quaternary amine” as used hereinbefore defines the quaternaryammonium salts which the compounds of formula (I) are able to form byreaction between a basic nitrogen of a compound of formula (I) and anappropriate quaternizing agent, such as, for example, an optionallysubstituted alkylhalide, arylhalide or arylalkylhalide, e.g.methyliodide or benzyliodide. Other reactants with good leaving groupsmay also be used, such as alkyl trifluoromethanesulfonates, alkylmethanesulfonates, and alkyl p-toluenesulfonates. A quaternary amine hasa positively charged nitrogen. Pharmaceutically acceptable counterionsinclude chloro, bromo, iodo, trifluoroacetate and acetate. Thecounterion of choice can be introduced using ion exchange resins.

The N-oxide forms of the present compounds are meant to comprise thecompounds of formula (I) wherein one or several tertiary nitrogen atomsare oxidized to the so-called N-oxide.

It will be appreciated that some of the compounds of formula (I) andtheir N-oxides, addition salts, quaternary amines and stereochemicallyisomeric forms may contain one or more centers of chirality and exist asstereochemically isomeric forms.

The term “stereochemically isomeric forms” as used hereinbefore definesall the possible stereoisomeric forms which the compounds of formula(I), and their N-oxides, addition salts, quaternary amines orphysiologically functional derivatives may possess. Unless otherwisementioned or indicated, the chemical designation of compounds denotesthe mixture of all possible stereochemically isomeric forms, saidmixtures containing all diastereomers and enantiomers of the basicmolecular structure as well as each of the individual isomeric forms offormula (I) and their N-oxides, salts, solvates or quaternary aminessubstantially free, i.e. associated with less than 10%, preferably lessthan 5%, in particular less than 2% and most preferably less than 1% ofthe other isomers. Thus, when a compound of formula (I) is for instancespecified as (E), this means that the compound is substantially free ofthe (Z) isomer.

In particular, stereogenic centers may have the R- or S-configuration;substituents on bivalent cyclic (partially) saturated radicals may haveeither the cis- or transconfiguration. Compounds encompassing doublebonds can have an E (entgegen) or Z (zusammen)-stereochemistry at saiddouble bond. The terms cis, trans, R, S, E and Z are well known to aperson skilled in the art.

Stereochemically isomeric forms of the compounds of formula (I) areobviously intended to be embraced within the scope of this invention.

For some of the compounds of formula (I), their prodrugs, N-oxides,salts, solvates, quaternary amines or metal complexes and theintermediates used in the preparation thereof, the absolutestereochemical configuration was not experimentally determined In thesecases the stereoisomeric form which was first isolated is designated as“A” and the second as “B”, without further reference to the actualstereochemical configuration. However, said “A” and “B” stereoisomericforms can be unambiguously characterized by for instance their opticalrotation in case “A” and “B” have an enantiomeric relationship. A personskilled in the art is able to determine the absolute configuration ofsuch compounds using art-known methods such as, for example, X-raydiffraction. In case “A” and “B” are stereoisomeric mixtures, they canbe further separated whereby the respective first fractions isolated aredesignated “A1” and “B1” and the second as “A2” and “B2”, withoutfurther reference to the actual stereochemical configuration.

Some of the compounds of formula (I) may also exist in their tautomericform. Such forms although not explicitly indicated in the above formulaare intended to be included within the scope of the present invention.

Whenever used hereinafter, the term “compounds of formula (I)” is meantto also include their N-oxide forms, their salts, their quaternaryamines and their stereochemically isomeric forms. Of special interestare those compounds of formula (I) which are stereochemically pure.

Whenever used hereinbefore or hereinafter that substituents can beselected each independently out of a list of numerous definitions, suchas for example for R⁹ and R¹⁰, all possible combinations are intendedwhich are chemically possible and which lead to chemically stablemolecules.

A particular group of compounds are those compounds of formula (I)wherein R³ is C₁₋₆alkyl substituted with at least one substituentselected from cyano, aminocarbonyl, NR⁹R¹⁰ or R⁷; C₁₋₆alkyl substitutedwith at least one substituent selected from cyano, aminocarbonyl, NR⁹R¹⁰or R⁷ and wherein 2 hydrogen atoms bound at the same carbon atom arereplaced by C₁₋₄alkanediyl; C₁₋₆alkyl substituted with hydroxy and asecond substituent selected from cyano, aminocarbonyl, NR⁹R¹⁰ or R⁷;C₁₋₆alkyloxyC₁₋₆alkyl substituted with at least one substituent selectedfrom cyano, aminocarbonyl, NR⁹R¹⁰ or R⁷; C₂₋₆alkenyl substituted with atleast one substituent selected from cyano, aminocarbonyl, NR⁹R¹⁰ or R⁷;C₂₋₆alkynyl substituted with at least one substituent selected fromcyano, aminocarbonyl, NR⁹R¹⁰ or R⁷; —C(═N—O—R⁸)—C₁₋₄alkyl; R⁷ or —X₃—R⁷;R⁴ is halo, hydroxy, C₁₋₆alkyl, C₃₋₇cycloalkyl, C₁₋₆alkyloxy, cyano,nitro, polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy, aminocarbonyl,C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonyl, formyl, amino, mono- ordi(C₁₋₄alkyl)amino; R⁷ is a monocyclic, bicyclic or tricyclic saturated,partially saturated or aromatic carbocycle or a monocyclic, bicyclic ortricyclic saturated, partially saturated or aromatic heterocycle,wherein each of said carbocyclic or heterocyclic ring systems mayoptionally be substituted with one, two, three, four or fivesubstituents each independently selected from halo, hydroxy, mercapto,C₁₋₆alkyl, hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl, mono ordi(C₁₋₆alkyl)aminoC₁₋₆alkyl, C₁₋₆alkylcarbonyl, C₃₋₇cycloalkyl,C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylthio, cyano, nitro,polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy, aminocarbonyl, R^(7a),—X₃—R^(7a) or R^(7a)—C₁₋₄alkyl; R^(7a) is a monocyclic, bicyclic ortricyclic saturated, partially saturated or aromatic carbocycle or amonocyclic, bicyclic or tricyclic saturated, partially saturated oraromatic heterocycle, wherein each of said carbocyclic or heterocyclicring systems may optionally be substituted with one, two, three, four orfive substituents each independently selected from halo, hydroxy,mercapto, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl, mono ordi(C₁₋₆alkyl)aminoC₁₋₆alkyl, C₁₋₆alkylcarbonyl, C₃₋₇cycloalkyl,C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylthio, cyano, nitro,polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy, aminocarbonyl; R⁹ and R¹⁰ eachindependently are hydrogen; hydroxy; C₁₋₆alkyl; C₁₋₆alkyloxy;C₁₋₆alkylcarbonyl; C₁₋₆alkyloxycarbonyl; amino; mono- ordi(C₁₋₆alkyl)amino; mono- or di(C₁₋₆alkyl)aminocarbonyl or R⁷, whereineach of the aforementioned C₁₋₆alkyl groups may optionally and eachindividually be substituted with one or two substituents eachindependently selected from hydroxy, C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy,carboxyl, C₁₋₆alkyloxycarbonyl, cyano, amino, imino, mono- ordi(C₁₋₄alkyl)amino, polyhalomethyl, polyhalomethyloxy,polyhalomethylthio, —S(═O)_(p)R⁶, —NH—S(═O)_(p)R⁶, —C(═O)R⁶, —NHC(═O)H,—C(═O)NHNH₂, —NHC(═O)R⁶, —C(═NH)R⁶, R⁷.

An interesting group of compounds are those compounds of formula (I)wherein -a¹=a²-a³=a⁴- represents a bivalent radical of formula—CH═CH—CH═CH—(a-1).

Also an interesting group of compounds are those compounds of formula(I) having the formula

the N-oxides, the pharmaceutically acceptable addition salts, thequaternary amines or the stereochemically isomeric forms thereof,wherein

-   -a¹=a²-a³=a⁴-, -b¹=b²-b³=b⁴-, R¹, R², R³, R⁴, m and X₁ are as    defined hereinabove;-   n′ is 0, 1, 2 or 3 and in case -a¹=a²-a³=a⁴- is (a-1), then n′ may    also be 4;-   R^(2′) is halo, C₁₋₆alkyl, trihalomethyl, cyano, aminocarbonyl,    C₁₋₆alkyl substituted with cyano or aminocarbonyl;-   provided that R^(2′) is placed at the para position in respect of    the NR¹ moiety.

Another interesting group of compounds are those compounds of formula(I) having the formula

the N-oxides, the pharmaceutically acceptable addition salts, thequaternary amines or the stereochemically isomeric forms thereof,wherein

-   -b¹=b²-b³=b⁴-, R¹, R², R³, R⁴, m and X₁ are as defined hereinabove;-   n′ is 0, 1, 2, 3 or 4;-   R^(2′) is halo, C₁₋₆alkyl, trihalomethyl, cyano, aminocarbonyl,    C₁₋₆alkyl substituted with cyano or aminocarbonyl.

Yet a further interesting group of compounds are those compounds offormula (I) having the formula

the N-oxides, the pharmaceutically acceptable addition salts, thequaternary amines or the stereochemically isomeric forms thereof,wherein

-   R¹, R², R³, R⁴ and X₁ are as defined hereinabove;-   n′ is 0, 1, 2, 3 or 4;-   R^(2′) is halo, C₁₋₆alkyl, trihalomethyl, cyano, aminocarbonyl,    C₁₋₆alkyl substituted with cyano or aminocarbonyl.

Also particular compounds are those compounds of formula (I), (I′), (I″)or (I′″) wherein one or wherever possible more of the followingconditions apply:

-   a) m is 1, 2 or 3, in particular 2 or 3, more in particular 2, even    more in particular m is 2 and said two R⁴ substituents are placed in    position 2 and 6 (ortho position) in respect of the X₁ moiety;-   b) m is 1, 2 or 3 and R³ is placed in position 4 (para position) in    respect of the X₁ moiety;-   c) X₁ is —NR^(S)—, —NH—NH—, —N═N—, —O—, —C(═O)—, C₁₋₄alkanediyl,    —CHOH—, —S(═O)_(p)—, —X₂—C₁₋₄alkanediyl- or —C₁₋₄alkanediyl-X₂—;-   d) where applicable n′ is 0;-   e) where applicable n is 1 and said R² substituent is placed in    position 4 (para position) in respect of the NR¹-linker;-   f) R² is hydroxy, halo, C₁₋₆alkyl optionally substituted with cyano    or —C(═O)R⁶, C₃₋₇cycloalkyl, C₂₋₆alkenyl optionally substituted with    one or more halogen atoms or cyano, C₂₋₆alkynyl optionally    substituted with one or more halogen atoms or cyano,    C₁₋₆alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono- or    di(C₁₋₆alkyl)amino, polyhalomethyl, polyhalomethylthio,    —S(═O)_(p)R⁶, —NH—S(═O)_(p)R⁶, —NHC(═O)H, —C(═O)NHNH₂, —NHC(═O)R⁶,    —C(═NH)R⁶ or a radical of formula

-   -   wherein each A₁ independently is N, CH or CR⁶; and        -   A₂ is NH, O, S or NR⁶;

-   g) R^(2′) is halo, C₁₋₆alkyl, trihalomethyl, cyano, C₁₋₆alkyl    substituted with cyano or aminocarbonyl;

-   h) R² is cyano, aminocarbonyl or C₁₋₆alkyl substituted with cyano or    aminocarbonyl, in particular cyano;

-   i) R^(2′) is cyano, aminocarbonyl or C₁₋₆alkyl substituted with    cyano or aminocarbonyl, in particular cyano.

A preferred embodiment encompasses those compounds of formula (I), (I′),(I″) or (I′″) wherein R³ is NHR¹³; NR¹³R¹⁴; —C(═O)—NHR¹³;—C(═O)—NR¹³R¹⁴; —C(═O)—R¹⁵; —CH═N—NH—C(═O)—R¹⁶; C₂₋₆alkyl substitutedwith cyano or aminocarbonyl; C₁₋₆alkyl substituted with NR⁹R¹⁰,—C(═O)—NR^(9a)R¹⁰, —C(═O)—C₁₋₆alkyl or R⁷; C₁₋₆alkyl substituted withtwo or more substituents each independently selected from cyano, NR⁹R¹⁰,—C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl or R⁷; C₁₋₆alkyl substituted with one ormore substituents each independently selected from cyano, NR⁹R¹⁰,—C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl or R⁷ and wherein 2 hydrogen atoms boundat the same carbon atom are replaced by C₁₋₄alkanediyl; C₁₋₆alkylsubstituted with hydroxy and a second substituent selected from cyano,NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl or R⁷; C₁₋₆alkyloxyC₁₋₆alkyloptionally substituted with one or more substituents each independentlyselected from cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl or R⁷;C₂₋₆alkenyl substituted with one or more substituents each independentlyselected from halo, cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl orR⁷; C₂₋₆alkynyl substituted with one or more substituents eachindependently selected from halo, cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰,—C(═O)—C₁₋₆alkyl or R⁷; —C(═N—O—R⁸)—C₁₋₄alkyl; R⁷ or —X₃—R⁷; with R^(9a)representing hydroxy; C₁₋₆alkyl; C₁₋₆alkyloxy; C₁₋₆alkylcarbonyl;C₁₋₆alkyloxycarbonyl; amino; mono- or di(C₁₋₆alkyl)amino; mono- ordi(C₁₋₆alkyl)aminocarbonyl, —CH(═NR¹¹) or R⁷, wherein each of theaforementioned C₁₋₆alkyl groups in the definition of R^(9a) mayoptionally and each individually be substituted with one or twosubstituents each independently selected from hydroxy, C₁₋₆alkyloxy,hydroxyC₁₋₆alkyloxy, carboxyl, C₁₋₆alkyloxycarbonyl, cyano, amino,imino, mono- or di(C₁₋₄alkyl)amino, polyhalomethyl, polyhalomethyloxy,polyhalomethylthio, —S(═O)_(p)R⁶, —NH—S(═O)_(p)R⁶, —C(═O)R⁶, —NHC(═O)H,—C(═O)NHNH₂, —NHC(═O)R⁶, —C(═NH)R⁶, R⁷; R^(9a) may also be takentogether with R¹⁰ to form a bivalent or trivalent radical of formula(d-1), (d-2), (d-3), (d-4), (d-5), (d-6) or (d-7) as definedhereinabove.

A further interesting group of compounds are those compounds of formula(I), (I′), (I″) or (I′″) wherein R³ is NHR¹³; NR¹³R¹⁴; —C(═O)—NHR¹³;—C(═O)—NR¹³R¹⁴; —C(═O)—R¹⁵; —CH═N—NH—C(═O)—R¹⁶; C₁₋₆alkyl substitutedwith NR⁹R¹⁰, —C(═O)—NR^(9a)R¹⁰, —C(═O)—C₁₋₆alkyl or R⁷; C₁₋₆alkylsubstituted with two or more substituents each independently selectedfrom cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl or R⁷; C₁₋₆alkylsubstituted with one or more substituents each independently selectedfrom cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl or R⁷ and wherein 2hydrogen atoms bound at the same carbon atom are replaced byC₁₋₄alkanediyl; C₁₋₆alkyl substituted with hydroxy and a secondsubstituent selected from cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkylor R⁷; C₁₋₆alkyloxyC₁₋₆alkyl optionally substituted with one or moresubstituents each independently selected from cyano, NR⁹R¹⁰,—C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl or R⁷; C₂₋₆alkenyl substituted with oneor more substituents each independently selected from halo, cyano,NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl or R⁷; C₂₋₆alkynyl substitutedwith one or more substituents each independently selected from halo,cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl or R⁷;—C(═N—O—R)—C₁₋₄alkyl; R⁷ or —X₃—R⁷; with R^(9a) representing hydroxy;C₁₋₆alkyl; C₁₋₆alkyloxy; C₁₋₆alkylcarbonyl; C₁₋₆alkyloxycarbonyl; amino;mono- or di(C₁₋₆alkyl)amino; mono- or di(C₁₋₆alkyl)aminocarbonyl,—CH(═NR¹¹) or R⁷, wherein each of the aforementioned C₁₋₆alkyl groups inthe definition of R^(9a) may optionally and each individually besubstituted with one or two substituents each independently selectedfrom hydroxy, C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy, carboxyl,C₁₋₆alkyloxycarbonyl, cyano, amino, imino, mono- or di(C₁₋₄alkyl)amino,polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, —S(═O)_(p)R⁶,—NH—S(═O)_(p)R⁶, —C(═O)R⁶, —NHC(═O)H, —C(═O)NHNH₂, —NHC(═O)R⁶,—C(═NH)R⁶, R⁷; R^(9a) may also be taken together with R¹⁰ to form abivalent or trivalent radical of formula (d-1), (d-2), (d-3), (d-4),(d-5), (d-6) or (d-7) as defined hereinabove.

Also an interesting group of compounds are those compounds of formula(I), (I′), (I″) or (I′″) wherein R³ is —CH═N—NH—C(═O)—R¹⁶; C₁₋₆alkylsubstituted with NR⁹R¹⁰, —C(═O)—NR^(9a)R¹⁰, —C(═O)—C₁₋₆alkyl or R⁷;C₁₋₆alkyl substituted with two or more substituents each independentlyselected from cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl or R⁷;C₁₋₆alkyl substituted with one or more substituents each independentlyselected from cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl or R⁷ andwherein 2 hydrogen atoms bound at the same carbon atom are replaced byC₁₋₄alkanediyl; C₁₋₆alkyl substituted with hydroxy and a secondsubstituent selected from cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkylor R⁷; C₁₋₆alkyloxyC₁₋₆alkyl optionally substituted with one or moresubstituents each independently selected from cyano, NR⁹R¹⁰,—C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl or R⁷; C₂₋₆alkenyl substituted with oneor more substituents each independently selected from halo, cyano,NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl or R⁷; C₂₋₆alkynyl substitutedwith one or more substituents each independently selected from halo,cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl or R⁷;—C(═N—O—R⁸)—C₁₋₄alkyl; R⁷ or —X₃—R⁷; with R^(9a) as defined hereinabove.

Another interesting group of compounds are those compounds of formula(I), (I′), (I″) or (I′″) wherein R³ is NHR¹³, NR¹³R¹⁴, —C(═O)—R¹⁵,C₁₋₆alkyl substituted with one or more substituents each independentlyselected from cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl or R⁷;C₁₋₆alkyl substituted with one or more substituents each independentlyselected from cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl or R⁷ andwherein 2 hydrogen atoms bound at the same carbon atom are replaced byC₁₋₄alkanediyl; C₁₋₆alkyl substituted with hydroxy and a secondsubstituent selected from cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkylor R⁷; C₁₋₆alkyloxyC₁₋₆alkyl optionally substituted with one or moresubstituents each independently selected from cyano, NR⁹R¹⁰,—C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl or R⁷; C₂₋₆alkenyl substituted with oneor more substituents each independently selected from halo, cyano,NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl or R⁷; C₂₋₆alkynyl substitutedwith one or more substituents each independently selected from halo,cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl or R⁷;—C(═N—O—R⁸)—C₁₋₄alkyl; R⁷ or —X₃—R⁷.

Also interesting are those compounds of formula (I), (I′), (I″) or (I′″)wherein R³ is C₁₋₆alkyl substituted with NR⁹R¹⁰, —C(═O)—NR^(9a)R¹⁰,—C(═O)—C₁₋₆alkyl or R⁷; C₁₋₆alkyl substituted with two or moresubstituents each independently selected from cyano, NR⁹R¹⁰,—C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl or R⁷; C₁₋₆alkyl substituted with one ormore substituents each independently selected from cyano, NR⁹R¹⁰,—C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl or R⁷ and wherein 2 hydrogen atoms boundat the same carbon atom are replaced by C₁₋₄alkanediyl; C₁₋₆alkylsubstituted with hydroxy and a second substituent selected from cyano,NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl or R⁷; C₁₋₆alkyloxyC₁₋₆alkyloptionally substituted with one or more substituents each independentlyselected from cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl or R⁷;C₂₋₆alkenyl substituted with one or more substituents each independentlyselected from halo, cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl orR⁷; C₂₋₆alkynyl substituted with one or more substituents eachindependently selected from halo, cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰,—C(═O)—C₁₋₆alkyl or R⁷; —C(═N—O—R)—C₁₋₄alkyl; R⁷ or —X₃—R⁷; with R^(9a)as defined hereinabove.

Also interesting are those compounds of formula (I), (I′), (I″) or (I′″)wherein R³ is C₁₋₆alkyl substituted with one or more substituents eachindependently selected from cyano, NR⁹R¹⁰ or R⁷; C₂₋₆alkenyl substitutedwith one or more substituents each independently selected from cyano,NR⁹R¹⁰ or R⁷; C₁₋₆alkyloxyC₁₋₆alkyl substituted with cyano; C₁₋₆alkylsubstituted with hydroxy and a second substituent selected from cyano orR⁷; —C(═N—O—R⁸)—C₁₋₄alkyl; R⁷ or —X₃—R⁷.

Another interesting group of compounds are those compounds of formula(I), (I′), (I″) or (I′″) wherein R³ is R⁷.

Still another interesting group of compounds are those compounds offormula (I), (I′), (I″) or (I′″) wherein R³ is C₁₋₆alkyl substitutedwith cyano, in particular C₂₋₆alkyl substituted with cyano, more inparticular ethyl or propyl substituted with cyano; or C₂₋₆alkenylsubstituted with cyano. Preferred is C₂₋₆alkenyl substituted with cyano.

Also an interesting group of compounds are those compounds of formula(I), (I′), (I″) or (I′″) wherein R³ is C₁₋₆alkyl substituted with cyanoand R⁷, or C₂₋₆alkenyl substituted with cyano and R⁷.

A further interesting group of compounds are those compounds of formula(I), (I′), (I″) or (I′″) wherein R³ is C₁₋₆alkyl substituted with R⁷.

Still a further interesting group of compounds are those compounds offormula (I), (I′), (I″) or (I′″) wherein R³ is —C(═N—O—R⁸)—C₁₋₄alkyl.

Also an interesting group of compounds are those compounds of formula(I), (I′), (I″) or (I′″) wherein R³ is C₁₋₆alkyl substituted withhydroxy and a second substituent selected from cyano or R⁷.

Also an interesting group of compounds are those compounds of formula(I), (I′), (I″) or (I′″) wherein R² or R^(2′) is cyano or aminocarbonyland R¹ is hydrogen.

Another interesting group of compounds are those compounds of formula(I), (I′), (I″) or (I′″) wherein m is 2 or 3 and X₁ is —NR⁵—, —O—,—C(═O)—, —CH₂—, —CHOH—, —S—, —S(═O)_(p)—, in particular wherein X₁ is—NR⁵—, or —O—.

Also an interesting group of compounds are those compounds of formula(I), (I′), (I″) or (I′″) wherein one or more, preferably all of thefollowing restrictions apply:

-   a) n is at least 1, in particular 1; or n′ is 0;-   b) R² or R^(2′) is cyano;-   c) m is 1, 2 or 3;-   d) R⁴ is C₁₋₆alkyl, especially methyl; nitro; amino; halo;    C₁₋₆alkyloxy or R⁷;-   e) R³ is R⁷, NR¹³R¹⁴, —C(═O)R¹⁵, —CH═N—NH—C(═O)R¹⁶, —C(═O)NHR¹³,    —C(═O)NR¹³R¹⁴, —C(═N—OR⁸)—C₁₋₄alkyl, C₁₋₆alkyl substituted with    cyano, C₁₋₆alkyl substituted twice with cyano, C₁₋₆alkyl substituted    with NR⁹R¹⁰, C₁₋₆alkyl substituted with hydroxy and cyano, C₁₋₆alkyl    substituted with hydroxy and R⁷, C₁₋₆alkyloxy C₁₋₆alkyl,    C₁₋₆alkyloxy C₁₋₆alkyl substituted with cyano, C₂₋₆alkenyl    substituted with R⁷, C₂₋₆alkenyl substituted with cyano, C₂₋₆alkenyl    substituted twice with cyano, C₂₋₆alkenyl substituted with cyano and    R⁷, C₂₋₆alkenyl substituted with cyano and —C(═O)—C₁₋₆alkyl,    C₂₋₆alkenyl substituted with cyano and halo, C₂₋₆alkenyl substituted    with —C(═O)—NR⁹R¹⁰, C₂₋₆alkenyl substituted with halo, C₂₋₆alkenyl    substituted twice with halo or C₂₋₆alkenyl substituted with NR⁹R¹⁰;-   f) X₃ is —C(═O)—, —CH₂—C(═O)—, or —C(═N—OR⁸)—C₁₋₄alkanediyl-;-   g) X₁ is NH or O;-   h) R¹ is hydrogen or C₁₋₄alkyl.

Preferred compounds of formula (I), (I′), (I″) or (I′″) are compounds 1,25, 84, 133, 152, 179, 233, 239, 247, 248 (see Tables 3, 4 and 5), theirN-oxides, pharmaceutically acceptable addition salts, quaternary aminesand stereochemically isomeric forms thereof.

In general, compounds of formula (I) can be prepared by reacting anintermediate of formula (II) wherein W₁ is a suitable leaving group suchas, for example, halo, triflate, tosylate, methylsulfonyl and the like,with an intermediate of formula (III). This reaction can be performed atelevated temperature.

Alternatively, the above reaction can be performed in the presence of asuitable solvent. Suitable solvents are for example acetonitrile, analcohol, such as for example ethanol, 2-propanol, 2-propanol-HCl;N,N-dimethylformamide; N,N-dimethylacetamide, 1-methyl-2-pyrrolidinone;1,4-dioxane, propyleneglycol monomethylether. Preferably the solvent is2-propanol, 6 N HCl in 2-propanol or acetonitrile, especiallyacetonitrile. Optionally, sodium hydride may be present.

In this and the following preparations, the reaction products may beisolated from the reaction medium and, if necessary, further purifiedaccording to methodologies generally known in the art such as, forexample, extraction, crystallization, distillation, trituration andchromatography.

Compounds of formula (I) wherein R³ is R⁷ representing a monocyclic,bicyclic or tricyclic aromatic ring system, said R³ being represented byR^(7′) and said compounds being represented by formula (I-a), can beprepared by reacting an intermediate of formula (IV) wherein W₂represents a suitable leaving group such as, for example, halo, hydroxy,triflate, tosylate, thiomethyl, methylsulfonyl, trifluoromethylsulfonyland the like, with an intermediate of formula (V) wherein R^(a)represents a boronate or a tri(C₁₋₄alkyl)stannane, such astributylstannane, in the presence of a suitable catalyst, such as forexample palladium tetrakis(triphenylphosphine), a suitable salt, such asfor example disodium carbonate, dipotassium carbonate, and Cs₂CO₃, and asuitable solvent, such as for example dioxane, dimethyl ether, tolueneor an alcohol/water mixture, e.g. MeOH/H₂O. R^(a) may also representhalo, such as for example bromo, in which case the reaction is performedin the presence of4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane.

Compounds of formula (I) wherein R³ is R⁷ representing a monocyclic,bicyclic or tricyclic saturated ring system, said R³ being representedby R^(7″) and said compounds being represented by formula (I-b), can beprepared by reacting an intermediate of formula (IV) with anintermediate of formula (VI).

Compounds of formula (I) wherein R³ represents C₁₋₆alkyl substitutedwith cyano, said R³ being represented by C₁₋₆alkyl-CN and said compoundsbeing represented by formula (I-c), can be prepared by reacting anintermediate of formula (VII) wherein W₃ represents a suitable leavinggroup, such as for example, halo, e.g. chloro, with a suitable cyanidesalt, such as for example sodium cyanide or potassium cyanide, in thepresence of a suitable solvent, such as for exampleN,N-dimethylformamide or dimethylsulfoxide.

Compounds of formula (I) wherein R³ represents C₁₋₆alkyl substitutedwith R⁷; NR⁹R¹⁰or C₁₋₆alkyloxy optionally substituted with CN, R⁷ orNR⁹R¹⁰, said R³ being represented by C₁₋₆alkyl-Q wherein Q representsR⁷; NR⁹R¹⁰ or C₁₋₆alkyloxy optionally substituted with CN, R⁷ or NR⁹R¹⁰,and said compounds being represented by formula (I-d), can be preparedby reacting an intermediate of formula (VII) with an intermediate offormula (VIII), optionally in the presence of a suitable salt, such asfor example dipotassium carbonate, potassium cyanide, potassium iodide,and a suitable solvent, such as for example acetonitrile.

Compounds of formula (I) wherein R³ represents —C(═N—O—R⁸)—C₁₋₄alkyl,said compounds being represented by formula (I-e), can be prepared byreacting an intermediate of formula (IX) with an intermediate of formula(X) in the presence of a suitable solvent, such as an alcohol, e.g.ethanol.

Compounds of formula (I) wherein R³ represents CR^(c′)═CR^(c)—CN whereinR^(c) represents hydrogen or C₁₋₄alkyl and R^(c′) represents hydrogen,C₁₋₄alkyl or R⁷, provided that CR^(c′)═CR^(c) is limited to C₂₋₆alkenyl,said compounds being represented by formula (I-f), can be prepared byreacting an intermediate of formula (XI) with a Wittig or Horner-Emmonsreagent of formula (XII), wherein R^(b)— represents for example(Phenyl)₃P⁺—CF⁻ or (CH₃CH₂—O)₂P(═O)—, which can be considered as asuitable precursor of a phosphorus ylide, in the presence of a suitablesalt, such as for example potassium tert.-butoxide, and a suitablesolvent, such as for example tetrahydrofuran.

Compounds of formula (I-f-1) and (I-f-2) as depicted below can beprepared by reacting an intermediate of formula (XXXIX) or anappropriate addition salt thereof, wherein W₅ represents a suitableleaving group, with acrylonitrile or acrylamide in the presence of asuitable palladium catalyst, a suitable base and a suitable solvent.

Suitable leaving groups in the above reaction are for example halo,triflate, tosylate, mesylate and the like. Preferably, W₅ is halo, moreparticularly iodo or bromo.

The palladium (Pd) catalyst may be a homogeneous Pd catalyst, such asfor example Pd(OAc)₂, PdCl₂, Pd(PPh₃)₄, Pd(PPh₃)₂Cl₂, bis(dibenzylideneacetone) palladium, palladium thiomethylphenylglutaramide metallacycleand the like, or a heterogeneous Pd catalyst, such as for examplepalladium on charcoal, palladium on metal oxides, palladium on zeolites.

Preferably, the palladium catalyst is a heterogeneous Pd catalyst, morepreferably palladium on charcoal (Pd/C). Pd/C is a recoverable catalyst,is stable and relatively inexpensive. It can be easily separated(filtration) from the reaction mixture thereby reducing the risk of Pdtraces in the final product. The use of Pd/C also avoids the need forligands, such as for example phosphine ligands, which are expensive,toxic and contaminants of the synthesized products.

Suitable bases in the above reaction are for example sodium acetate,potassium acetate, N,N-diethylethanamine, sodium hydrogencarbonate,sodium hydroxide and the like.

Suitable solvents in the above reaction are for example acetonitrile,N,N-dimethylacetamide, an ionic liquid e.g. [bmim]PF₆,N,N-dimethylformamide, water, tetrahydrofuran, dimethylsulphoxide,1-methyl-2-pyrrolidinone and the like.

Compounds of formula (I) wherein R³ represents CR^(c)═CR^(c″)—CN withR^(c) being as defined hereinabove and R^(c″) representing NR⁹R¹⁰,—C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl or R⁷, said compounds being representedby formula (I-g), can be prepared by reacting an intermediate of formula(XI-a) with an intermediate of formula (XIII) in the presence of asuitable solvent, such as for example an alcohol and an alcoholate, e.g.methanol and sodium ethanolate.

Compounds of formula (I) wherein R³ represents CH═C(CN)—CH₂—CN, saidcompounds being represented by formula (I-h), can be prepared byreacting an intermediate of formula (XI-b) with 2-butenedinitrile in thepresence of tributylphosphine and a suitable solvent, such as forexample tetrahydrofuran.

Compounds of formula (I) wherein R³ represents CH═C(CN)₂, said compoundsbeing represented by formula (I-h′), can be prepared by reacting anintermediate of formula (XI-b) with propanedinitrile in the presence ofa suitable base, such as for example piperidine, and a suitable solvent,such as for example an alcohol, e.g. ethanol and the like.

Compounds of formula (I) wherein R³ represents —CHOH—CH₂—CN, saidcompounds being represented by formula (I-i), can be prepared byreacting an intermediate of formula (XI-b) with CH₃—CN in the presenceof a suitable proton-abstracting agent, such as for example butyllithium, in the presence of a suitable substrate for theproton-abstracting agent, for example N-(1-methylethyl)-2-propanamine,and in the presence of a suitable solvent, such as for exampletetrahydrofuran.

Compounds of formula (I) wherein R³ represents CR^(c′)═CR^(c)-halowherein R^(c) represents hydrogen or C₁₋₄alkyl and R^(c′) representshydrogen, C₁₋₄alkyl or R⁷, provided that CR^(c′)═CR^(c) is limited toC₂₋₆alkenyl, said compounds being represented by formula (I-j), can beprepared by reacting an intermediate of formula (XI) with a Wittig orHorner-Emmons reagent of formula (XII′), wherein R^(b)— represents forexample (Phenyl)₃P⁺—Cl⁻ or (CH₃CH₂—O)₂P(═O)—, which can be considered asa suitable precursor of a phosphorus ylide, in the presence of nBuLi,and a suitable solvent, such as for example tetrahydrofuran.

Compounds of formula (I) wherein R³ represents CR^(c)═CR^(c″)-halo withR^(c) being as defined hereinabove and R^(c′″) representing CN, NR⁹R¹⁰,—C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl or R⁷, said compounds being representedby formula (I-k), can be prepared by reacting an intermediate of formula(XI-a) with an intermediate of formula (XIII-a) in the presence of aHorner-Emmons reagent such as for example (CH₃CH₂—O)₂P(═O)—Cl, nBuLi,1,1,1-trimethyl-N-(trimethylsilyl)-silanamine, and a suitable solvent,such as for example tetrahydrofuran.

Compounds of formula (I) wherein R³ represents CH═C(Br)₂, said compoundsbeing represented by formula (I-1), can be prepared by reacting anintermediate of formula (XVIII) with CBr₄, in the presence of a suitablecatalyst salt, such as for example (CuCl)₂, and in the presence of asuitable base, such as for example NH₃, and a suitable solvent, such asfor example dimethylsulfoxide.

Compounds of formula (I-m) can be prepared by reacting an intermediateof formula (XIV) with Cl₂C═S in the presence of a suitable solvent, suchas for example dioxane.

Compounds of formula (I-n) can be prepared by reacting an intermediateof formula (XV) with an intermediate of formula (XVI) in the presence ofa suitable solvent, such as for example an alcohol or an alcoholate,e.g. ethanol or sodium methanolate.

Compounds of formula (I) wherein R³ represents C₂₋₆alkenyl substitutedwith C(═O)NR⁹R¹⁰ and optionally further substituted with cyano, saidcompounds being represented by formula (I-o) wherein C₂₋₆alkenyl′represents C₂₋₆alkenyl optionally substituted with cyano, can beprepared by reacting an intermediate of formula (XXIX) with anintermediate of formula (XXX) in the presence of hydroxybenzotriazoleand ethyldimethylaminopropyl carbodiimide and a suitable solvent, suchas for example methylene chloride or tetrahydrofuran, and optionally inthe presence of a suitable base, such as for exampleN,N-diethylethanamine, NH₄OH and the like.

Compounds of formula (I) wherein R³ represents —C(═O)NR¹³R¹⁴ or—C(═O)NHR¹³, said compounds being represented by formula (I-p-1) and(I-p-2) can be prepared by reacting an intermediate of formula (XXXI)with an intermediate of formula (XXXII-1) or (XXXII-2) in the presenceof hydroxybenzotriazole and ethyldimethylaminopropyl carbodiimide and asuitable solvent, such as for example methylene chloride ortetrahydrofuran, and optionally in the presence of a suitable base, suchas for example N,N-diethylethanamine.

Compounds of formula (I) wherein R³ represents CH═N—NH—C(═O)—R¹⁶, saidcompounds being represented by formula (I-q), can be prepared byreacting an intermediate of formula (XI-b) with an intermediate offormula (XXXIII) in the presence of a suitable solvent, such as forexample methylene chloride and an alcohol, e.g. methanol, ethanol andthe like.

Compounds of formula (I) wherein R³ represents N(CH₃)₂, said compoundsbeing represented by formula (I-r), can be prepared by reductivemethylation of an intermediate of formula (XXXIV) with formaldehyde inthe presence of a suitable catalyst, such as for example a suitableacid, i.e. acetic acid and the like, palladium on charcoal, RaneyNickel, and in the presence of a suitable reductive agent, such as forexample sodium cyanoborohydride or H₂, and a suitable solvent, such asfor example acetonitrile.

Compounds of formula (I) wherein R³ represents pyrrolyl, said compoundsbeing represented by formula (I-s), can be prepared by reacting anintermediate of formula (XXXIV) with 2,5-dimethoxytetrahydrofuran in thepresence of a suitable acid, such as for example acetic acid.

Compounds of formula (I) wherein R³ represents CH═CH—R⁷, said compoundsbeing represented by formula (I-t), can be prepared by reacting anintermediate of formula (XXXV) (Ph indicates phenyl) with anintermediate of formula (XXXVI) in the presence of nBuLi and a suitablesolvent, such as for example tetrahydrofuran.

The compounds of formula (I) may further be prepared by convertingcompounds of formula (I) into each other according to art-known grouptransformation reactions.

The compounds of formula (I) may be converted to the correspondingN-oxide forms following art-known procedures for converting a trivalentnitrogen into its N-oxide form. Said N-oxidation reaction may generallybe carried out by reacting the starting material of formula (I) with anappropriate organic or inorganic peroxide. Appropriate inorganicperoxides comprise, for example, hydrogen peroxide, alkali metal orearth alkaline metal peroxides, e.g. sodium peroxide, potassiumperoxide; appropriate organic peroxides may comprise peroxy acids suchas, for example, benzenecarboperoxoic acid or halo substitutedbenzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid,peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g.tert.butyl hydro-peroxide. Suitable solvents are, for example, water,lower alcohols, e.g. ethanol and the like, hydrocarbons, e.g. toluene,ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g.dichloromethane, and mixtures of such solvents.

For instance, a compound of formula (I) wherein R³ comprises cyano, canbe converted into a compound of formula (I) wherein R³ comprisesaminocarbonyl, by reaction with HCOOH, in the presence of a suitableacid, such as hydrochloric acid. A compound of formula (I) wherein R³comprises cyano, can also further be converted into a compound offormula (I) wherein R³ comprises tetrazolyl, by reaction with sodiumazide in the presence of ammonium chloride and N,N-dimethylacetamide.

Compounds of formula (I) wherein R³ comprises aminocarbonyl, can beconverted into a compound of formula (I) wherein R³ comprises cyano, inthe presence of a suitable dehydrating agent. The dehydration can beperformed according to methodologies well-known to the person skilled inthe art, such as the ones disclosed in “Comprehensive OrganicTransformations. A guide to functional group preparations” by Richard C.Larock, John Wiley & Sons, Inc, 1999, p 1983-1985, which is incorporatedherein as reference. Different suitable reagents are enumerated in saidreference, such as for example SOCl₂, HOSO₂NH₂, ClSO₂NCO, MeO₂CNSO₂NEt₃, PhSO₂Cl, TsCl, P₂O₅, (Ph₃PO₃SCF₃)O₃SCF₃, polyphosphate ester,(EtO)₂POP(OEt)₂, (EtO)₃PI₂, 2-chloro-1,3,2-dioxaphospholane,2,2,2-trichloro-2,2-dihydro-1,3,2-dioxaphospholane, POCl₃, PPh₃,P(NCl₂)₃, P(NEt₂)₃, COCl₂, NaCl.AlCl₃, ClCOCOCl, ClCO₂Me, Cl₃CCOCl,(CF₃CO)₂O, Cl₃CN═CCl₂, 2,4,6-trichloro-1,3,5-triazine, NaCl.AlCl₃,HN(SiMe₂)₃, N(SiMe₂)₄, LiAlH₄ and the like. All the reagents listed insaid publication are incorporated herein as reference.

Compounds of formula (I) wherein R³ comprises C₂₋₆alkenyl can beconverted into a compound of formula (I) wherein R³ comprises C₁₋₆alkylby reduction in the presence of a suitable reducing agent, such as forexample H₂, in the presence of a suitable catalyst, such as for examplepalladium on charcoal, and in the presence of a suitable solvent, suchas for example an alcohol, e.g. methanol.

Compounds of formula (I) wherein R³ represents CH(OH)—R¹⁶, can beconverted into a compound of formula (I) wherein R³ represents C(═O)—R¹⁶by reaction with Jones's reagent in the presence of a suitable solvent,such as for example 2-propanone.

Compound of formula (I) wherein R³ represents C(═O)—CH₂—R^(16a), whereinR^(16a) represents cyano or aminocarbonyl, can be converted into acompound of formula (I) wherein R³ represents C(Cl)═CH—R^(16a) byreaction with POCl₃.

Compounds of formula (I) wherein R³ represents a monocyclic, bicyclic ortricyclic saturated, partially saturated or aromatic carbocycle or amonocyclic, bicyclic or tricyclic saturated, partially saturated oraromatic heterocycle substituted with formyl can be converted intocompounds of formula (I) wherein R³ represents a monocyclic, bicyclic ortricyclic saturated, partially saturated or aromatic carbocycle or amonocyclic, bicyclic or tricyclic saturated, partially saturated oraromatic heterocycle substituted with CH(═N—O—R⁸) by reaction withNH₂OR⁸ in the presence of a suitable base, such as for example sodiumhydroxide and a suitable solvent, such as for example an alcohol, e.g.ethanol and the like. Compounds of formula (I) wherein R³ represents amonocyclic, bicyclic or tricyclic saturated, partially saturated oraromatic carbocycle or a monocyclic, bicyclic or tricyclic saturated,partially saturated or aromatic heterocycle substituted with CH(═N—O—R⁸)can be converted into a compound of formula (I) wherein R³ represents amonocyclic, bicyclic or tricyclic saturated, partially saturated oraromatic carbocycle or a monocyclic, bicyclic or tricyclic saturated,partially saturated or aromatic heterocycle substituted with CN byreaction with a carbodiimide in the presence of a suitable solvent, suchas for example tetrahydrofuran.

Compounds of formula (I) wherein R⁴ represents nitro, can be convertedinto a compound of formula (I) wherein R⁴ is amino, in the presence of asuitable reducing agent, such as for example H₂, in the presence of asuitable catalyst, such as for example Raney Nickel, and in the presenceof a suitable solvent, such as for example an alcohol, e.g. methanol.

Compounds of formula (I) wherein R¹ is hydrogen, can be converted into acompound of formula (I) wherein R¹ is C₁₋₆alkyl, by reaction with asuitable alkylating agent, such as for example iodo-C₁₋₆alkyl, in thepresence of a suitable base, such as for example sodium hydride, and asuitable solvent, such as for example tetrahydrofuran. Some of thecompounds of formula (I) and some of the intermediates in the presentinvention may contain an asymmetric carbon atom. Pure stereochemicallyisomeric forms of said compounds and said intermediates can be obtainedby the application of art-known procedures. For example,diastereoisomers can be separated by physical methods such as selectivecrystallization or chromatographic techniques, e.g. counter currentdistribution, liquid chromatography and the like methods. Enantiomerscan be obtained from racemic mixtures by first converting said racemicmixtures with suitable resolving agents such as, for example, chiralacids, to mixtures of diastereomeric salts or compounds; then physicallyseparating said mixtures of diastereomeric salts or compounds by, forexample, selective crystallization or chromatographic techniques, e.g.liquid chromatography and the like methods; and finally converting saidseparated diastereomeric salts or compounds into the correspondingenantiomers. Pure stereochemically isomeric forms may also be obtainedfrom the pure stereochemically isomeric forms of the appropriateintermediates and starting materials, provided that the interveningreactions occur stereospecifically.

An alternative manner of separating the enantiomeric forms of thecompounds of formula (I) and intermediates involves liquidchromatography, in particular liquid chromatography using a chiralstationary phase.

Some of the intermediates and starting materials are known compounds andmay be commercially available or may be prepared according to art-knownprocedures or some of the compounds of formula (I) or the describedintermediates may be prepared according to the procedures described inWO 99/50250 and WO 00/27825.

Intermediates of formula (II) can be prepared by reacting anintermediate of formula (XVII) with a leaving group introducing agent offormula (XIX) wherein W₁ represents the leaving group and R representsthe remaining of the leaving group introducing agent, such as forexample POCl₃.

Intermediates of formula (III) wherein X₁ represents NH, saidintermediates being represented by formula (III-a), can be prepared froman intermediate of formula (XX) in the presence of ZnCl₂ and in thepresence of a suitable solvent, such as for example an alcohol, forexample ethanol.

Intermediates of formula (III′-a) as depicted below can be prepared froman intermediate of formula (XX) wherein R³ represents C₂₋₆alkenylsubstituted with CN, said intermediate being represented by formula(XX-a), in the presence of ZnCl₂ and in the presence of a suitableC₁₋₄alkyl-OH, such as for example ethanol.

Intermediates of formula (III-b-1) and (III-b-2) as depicted below canbe prepared by reacting an intermediate of formula (XLI) or anappropriate acid addition salt thereof, wherein W₆ represents a suitableleaving group, with acrylonitrile or acrylamide in the presence of asuitable palladium catalyst a suitable base and a suitable solvent.

Suitable leaving groups in the above reaction are for example halo,triflate, tosylate, mesylate and the like. Preferably, W₆ is halo, morepreferably iodo or bromo.

The palladium (Pd) catalyst may be a homogeneous Pd catalyst, such asfor example Pd(OAc)₂, PdCl₂, Pd(PPh₃)₄, Pd(PPh₃)₂Cl₂, bis(dibenzylideneacetone) palladium, palladium thiomethylphenylglutaramide metallacycleand the like, or a heterogeneous Pd catalyst, such as for examplepalladium on charcoal, palladium on metal oxides, palladium on zeolites.

Preferably, the palladium catalyst is a heterogeneous Pd catalyst, morepreferably palladium on charcoal (Pd/C). Pd/C is a recoverable catalyst,is stable and relatively inexpensive. It can be easily separated(filtration) from the reaction mixture thereby reducing the risk of Pdtraces in the final product. The use of Pd/C also avoids the need forligands, such as for example phosphine ligands, which are expensive,toxic and contaminants of the synthesized products.

Suitable bases in the above reaction are for example sodium acetate,potassium acetate, N,N-diethylethanamine, sodium hydrogencarbonate,sodium hydroxide and the like.

Suitable solvents in the above reaction are for example acetonitrile,N,N-dimethylacetamide, an ionic liquid e.g. [bmim]PF₆,N,N-dimethylformamide, water, tetrahydrofuran, dimethylsulphoxide,1-methyl-2-pyrrolidinone and the like.

Intermediates of formula (III-b-2) can be converted into an intermediateof formula (III-b-1) in the presence of a suitable dehydrating agent.The dehydration can be performed according to methodologies well-knownto the person skilled in the art, such as the ones disclosed in“Comprehensive Organic Transformations. A guide to functional grouppreparations” by Richard C. Larock, John Wiley & Sons, Inc, 1999, p1983-1985, which is incorporated herein as reference. Different suitablereagents are enumerated in said reference, such as for example SOCl₂,HOSO₂NH₂, ClSO₂NCO, MeO₂CNSO₂NEt₃, PhSO₂Cl, TsCl, P₂O₅,(Ph₃PO₃SCF₃)O₃SCF₃, polyphosphate ester, (EtO)₂POP(OEt)₂, (EtO)₃PI₂,2-chloro-1,3,2-dioxaphospholane,2,2,2-trichloro-2,2-dihydro-1,3,2-dioxaphospholane, POCl₃, PPh₃,P(NCl₂)₃, P(NEt₂)₃, COCl₂, NaCl.AlCl₃, ClCOCOCl, ClCO₂Me, Cl₃CCOCl,(CF₃CO)₂O, Cl₃CN═CCl₂, 2,4,6-trichloro-1,3,5-triazine, NaCl.AlCl₃,HN(SiMe₂)₃, N(SiMe₂)₄, LiAlH₄ and the like. All the reagents listed insaid publication are incorporated herein as reference.

Intermediates of formula (XX) wherein R³ represents CR^(c′)═CR^(c)—CNwith R^(c)C and R^(c′) as described hereinabove, said intermediatesbeing represented by formula (XX-b), can be prepared from anintermediate of formula (XXI) by the reaction described above for thepreparation of a compound of formula (I-f).

Intermediates of formula (XXI) can be prepared by oxidation of anintermediate of formula (XXII) in the presence of a suitable oxidizingagent, such as for example KMnO₄, in the presence of a suitable solvent,such as for example methylene chloride andtris[2-(2-methoxyethoxy)ethyl]amine.

Intermediates of formula (XXI) wherein R^(c′) is H, said intermediatesbeing represented by formula (XXI-a), can also be prepared by reactingan intermediate of formula (XXIII) wherein W₄ represents a suitableleaving group, such as halo, e.g. bromo, with N,N-dimethylformamide inthe presence of nBuLi and in the presence of a suitable solvent, such asfor example tetrahydrofuran.

Intermediates of formula (XXII) wherein R^(c′) represents C₁₋₄alkyl,said intermediates being represented by formula (XXII-a), can beprepared by reacting an intermediate of formula (XXIII) with anintermediate of formula (XXIV) in the presence of nBuLi and in thepresence of a suitable solvent, such as for example tetrahydrofuran.

Intermediates of formula (XI) can be prepared by reacting anintermediate of formula (XXV) with an intermediate of formula (II),optionally in the presence of a suitable base, such as for example1-methyl-pyrrolidin-2-one, or a suitable acid, such as for examplehydrochloric acid.

Intermediates of formula (XV) can be prepared by reacting anintermediate of formula (XXVI) with an intermediate of formula (II) inthe presence of a suitable base, such as for example1-methyl-pyrrolidin-2-one and sodium hydride and a suitable solvent,such as for example dioxane.

Intermediates of formula (VII) can be prepared by reacting anintermediate of formula (XXVII) with a leaving group introducing agentof formula (XIX′), such as for example SOCl₂, in the presence of asuitable solvent, such as for example methylene chloride.

Intermediates of formula (XXVII) wherein C₁₋₆alkyl represents CH₂, saidintermediates being represented by formula (XXVII-a), can be prepared byreducing an intermediate of formula (XV) or formula (XXXI) with asuitable reducing agent, such as for example LiAlH₄, in the presence ofa suitable solvent, such as for example tetrahydrofuran.

Intermediates of formula (XXVII-a) can be converted to an intermediateof formula (XXXI) by reaction with Jones reagent in the presence of asuitable solvent, such as for example acetone.

Intermediates of formula (XI-b) can be prepared by oxidizing anintermediate of formula (XXVII-a) in the presence of a suitableoxidizing agent, such as for example MnO₂, and a suitable solvent, suchas for example methylene chloride, N,N-dimethylformamide.

Intermediates of formula (XIV) can be prepared by reacting anintermediate of formula (XV) with H₂N—NH₂ in the presence of a suitablesolvent, such as for example an alcohol, e.g. ethanol and the like.

Intermediates of formula (IX) and (XI-a) can be reduced to anintermediate of formula (XXVII′-a) and (XXVII′-b) in the presence of asuitable reducing agent, such as for example NaBH₄, LiAlH₄ or BuLi and asuitable solvent, such as for example tetrahydrofuran or an alcohol,e.g. methanol, ethanol and the like.

An intermediate of formula (XI-b) can be converted into an intermediateof formula (XXVII′-a) by reaction with C₁₋₄alkyl-Iodide in the presenceof Mg and a suitable solvent, such as for example diethylether andtetrahydrofuran.

Intermediates of formula (XVIII) can be prepared by reacting anintermediate of formula (XI-b) with H₂N—NH₂ in the presence of asuitable solvent, such as for example an alcohol, e.g. ethanol and thelike.

Intermediates of formula (XXIX) or (XXXI) can be prepared by hydrolizingan intermediate of formula (XXXVII) wherein C₂₋₆alkenyl′ representsC₂₋₆alkenyl optionally substituted cyano, or an intermediate of formula(XV) in the presence of a suitable aqueous acid solution, such as forexample hydrochloric acid 2N and the like, and in the presence of asuitable solvent, such as for example an alcohol, e.g. isopropanol andthe like.

Intermediates of formula (XXXVII) wherein C₂₋₆alkenyl is CH═CH, saidintermediates being represented by formula (XXXVII-a), can be preparedby reacting an intermediate of formula (XI-b) with a Wittig orHorner-Emmons reagent of formula (XII″), wherein R^(b) represents forexample (Phenyl)₃P⁺—Cl⁻ or (CH₃CH₂—O)₂P(═O)—, which can be considered asa suitable precursor of a phosphorus ylide, in the presence of asuitable solvent, such as for example tetrahydrofuran.

Intermediates of formula (XXXVII) wherein C₂₋₆alkenyl′ is —CH═C(CN)—,said intermediates being represented by formula (XXXVII-b), can beprepared by reacting an intermediate of formula (XI-b) with

NC—CH₂—C(═O)O—C₁₋₆alkyl, in the presence of a suitable base, such as forexample piperidine, and a suitable solvent, such as for example analcohol, e.g. ethanol.

Intermediates of formula (XXXIV) can be prepared by reducing anintermediate of formula (XXXVIII) in the presence H₂ and a suitablecatalyst, such as for example palladium on charcoal or Raney Nickel, andin the presence of a suitable solvent, such as for example an alcohol,e.g. methanol and the like.

Intermediates of formula (XXXV) can be prepared by reacting anintermediate of formula (VII-a) in the presence of triphenylphosphineand a suitable solvent, such as for example acetonitrile.

Intermediates of formula (XXXIX) can be prepared by reacting anintermediate of formula (XL) with an intermediate of formula (II-a)wherein W₅ and W₁ are as defined hereinbefore.

The compounds of formula (I) as prepared in the hereinabove describedprocesses may be synthesized as a mixture of stereoisomeric forms, inparticular in the form of racemic mixtures of enantiomers which can beseparated from one another following art-known resolution procedures.The racemic compounds of formula (I) may be converted into thecorresponding diastereomeric salt forms by reaction with a suitablechiral acid. Said diastereomeric salt forms are subsequently separated,for example, by selective or fractional crystallization and theenantiomers are liberated therefrom by alkali. An alternative manner ofseparating the enantiomeric forms of the compounds of formula (I)involves liquid chromatography using a chiral stationary phase. Saidpure stereochemically isomeric forms may also be derived from thecorresponding pure stereochemically isomeric forms of the appropriatestarting materials, provided that the reaction occursstereospecifically. Preferably if a specific stereoisomer is desired,said compound will be synthesized by stereospecific methods ofpreparation. These methods will advantageously employ enantiomericallypure starting materials.

It will be appreciated by those skilled in the art that in the processesdescribed above the functional groups of intermediate compounds may needto be blocked by protecting groups.

Functional groups which it is desirable to protect include hydroxy,amino and carboxylic acid. Suitable protecting groups for hydroxyinclude trialkylsilyl groups (e.g. tert-butyldimethylsilyl,tert-butyldiphenylsilyl or trimethylsilyl), benzyl andtetrahydropyranyl. Suitable protecting groups for amino includetert-butyloxycarbonyl or benzyloxycarbonyl. Suitable protecting groupsfor carboxylic acid include C₁₋₆alkyl or benzyl esters.

The protection and deprotection of functional groups may take placebefore or after a reaction step.

The use of protecting groups is fully described in ‘Protective Groups inOrganic Chemistry’, edited by J W F McOmie, Plenum Press (1973), and‘Protective Groups in Organic Synthesis’ 2^(nd) edition, T W Greene & PG M Wutz, Wiley Interscience (1991).

The present invention also concerns new compounds of formula (VII),(XXVII), (XXIX) and (XXXVII) which can be used as intermediates in thesynthesis of the compounds of formula (I) and which also exhibit HIVreplication inhibiting activity.

In particular, the present invention also relates to a compound offormula

-   a N-oxide, a pharmaceutically acceptable addition salt, a quaternary    amine and a stereochemically isomeric form thereof, wherein-   R¹, R², R⁴, X₁, m, n, -a=a²-a³=a⁴- and -b¹=b²-b³=b⁴- are as defined    hereinabove for the compounds of formula (I) and W₃ represents a    suitable leaving group such as for example halo, e.g. chloro and the    like.

The present invention also relates to a compound of formula

-   a N-oxide, a pharmaceutically acceptable addition salt, a quaternary    amine and a stereochemically isomeric form thereof, wherein-   R¹, R², R⁴, X₁, m, n, -a¹=a²-a³=a⁴- and -b=b²-b³=b⁴- are as defined    hereinabove for the compounds of formula (I).

The present invention also relates to a compound of formula

-   a N-oxide, a pharmaceutically acceptable addition salt, a quaternary    amine and a stereochemically isomeric form thereof, wherein-   R¹, R², R⁴, X₁, m, n, -a¹=a²-a³=a⁴- and -b=b²-b³=b⁴- are as defined    hereinabove for the compounds of formula (I) and C₂₋₆alkenyl′    represents C₂₋₆alkenyl optionally substituted with cyano.

The present invention also relates to a compound of formula

-   a N-oxide, a pharmaceutically acceptable addition salt, a quaternary    amine and a stereochemically isomeric form thereof, wherein-   R¹, R², R⁴, X₁, m, n, -a¹=a²-a³=a⁴- and -b=b²-b³=b⁴- are as defined    hereinabove for the compounds of formula (I) and C₂₋₆alkenyl′    represents C₂₋₆alkenyl optionally substituted with cyano.

Compounds of formula (III-b) as depicted below intervene in thesynthesis of compounds of formula (I).

Therefore, the present invention also relates to a compound of formula(III-b)

-   a N-oxide, a pharmaceutically acceptable addition salt, a quaternary    amine and a stereochemically isomeric form thereof, wherein-   R⁴ and X₁ are as defined hereinabove for the compounds of formula    (I).

Preferred compounds of formula (III-b) are those compounds wherein X₁represents NH. More preferred compounds of formula (III-b) are thosecompounds wherein X₁ represents NH and C₂₋₆alkenyl represents CH═CH.Most preferred compounds of formula (III-b) are the compounds of formula(III-b-1) as described hereinabove.

The compounds of formula (I), (I′), (I″), (I′″), (VII), (XXVII), (XXIX)and (XXXVII) show antiretroviral properties (reverse transcriptaseinhibiting properties), in particular against Human ImmunodeficiencyVirus (HIV), which is the aetiological agent of Acquired ImmuneDeficiency Syndrome (AIDS) in humans. The HIV virus preferentiallyinfects human T-4 cells and destroys them or changes their normalfunction, particularly the coordination of the immune system. As aresult, an infected patient has an ever decreasing number of T-4 cells,which moreover behave abnormally. Hence, the immunological defensesystem is unable to combat infections and neoplasms and the HIV infectedsubject usually dies by opportunistic infections such as pneumonia, orby cancers. Other conditions associated with HIV infection includethrombocytopaenia, Kaposi's sarcoma and infection of the central nervoussystem characterized by progressive demyelination, resulting in dementiaand symptoms such as, progressive dysarthria, ataxia and disorientation.HIV infection further has also been associated with peripheralneuropathy, progressive generalized lymphadenopathy (PGL) andAIDS-related complex (ARC).

The present compounds also show activity against (multi) drug resistantHIV strains, in particular (multi) drug resistant HIV-1 strains, more inparticular the present compounds show activity against HIV strains,especially HIV-1 strains, that have acquired resistance to one or moreart-known non-nucleoside reverse transcriptase inhibitors. Art-knownnon-nucleoside reverse transcriptase inhibitors are those non-nucleosidereverse transcriptase inhibitors other than the present compounds and inparticular commercial non-nucleoside reverse transcriptase inhibitors.The present compounds also have little or no binding affinity to humanα-1 acid glycoprotein; human α-1 acid glycoprotein does not or onlyweakly affect the anti HIV activity of the present compounds.

Due to their antiretroviral properties, particularly their anti-HIVproperties, especially their anti-HIV-1-activity, the compounds offormula (I), their N-oxides, pharmaceutically acceptable addition salts,quaternary amines and stereochemically isomeric forms thereof, areuseful in the treatment of individuals infected by HIV and for theprophylaxis of these infections. In general, the compounds of thepresent invention may be useful in the treatment of warm-blooded animalsinfected with viruses whose existence is mediated by, or depends upon,the enzyme reverse transcriptase. Conditions which may be prevented ortreated with the compounds of the present invention, especiallyconditions associated with HIV and other pathogenic retroviruses,include AIDS, AIDS-related complex (ARC), progressive generalizedlymphadenopathy (PGL), as well as chronic Central Nervous Systemdiseases caused by retroviruses, such as, for example HIV mediateddementia and multiple sclerosis.

The compounds of the present invention or any subgroup thereof maytherefore be used as medicines against above-mentioned conditions. Saiduse as a medicine or method of treatment comprises the administration toHIV-infected subjects of an amount effective to combat the conditionsassociated with HIV and other pathogenic retroviruses, especially HIV-1.In particular, the compounds of formula (I) may be used in themanufacture of a medicament for the treatment or the prevention of HIVinfections.

In view of the utility of the compounds of formula (I), there isprovided a method of treating warm-blooded animals, including humans,suffering from or a method of preventing warm-blooded animals, includinghumans, to suffer from viral infections, especially HIV infections. Saidmethod comprises the administration, preferably oral administration, ofan effective amount of a compound of formula (I), a N-oxide form, apharmaceutically acceptable addition salt, a quaternary amine or apossible stereoisomeric form thereof, to warm-blooded animals, includinghumans.

The present invention also provides compositions for treating viralinfections comprising a therapeutically effective amount of a compoundof formula (I) and a pharmaceutically acceptable carrier or diluent.

The compounds of the present invention or any subgroup thereof may beformulated into various pharmaceutical forms for administrationpurposes. As appropriate compositions there may be cited allcompositions usually employed for systemically administering drugs. Toprepare the pharmaceutical compositions of this invention, an effectiveamount of the particular compound, optionally in addition salt form, asthe active ingredient is combined in intimate admixture with apharmaceutically acceptable carrier, which carrier may take a widevariety of forms depending on the form of preparation desired foradministration. These pharmaceutical compositions are desirable inunitary dosage form suitable, particularly, for administration orally,rectally, percutaneously, or by parenteral injection. For example, inpreparing the compositions in oral dosage form, any of the usualpharmaceutical media may be employed such as, for example, water,glycols, oils, alcohols and the like in the case of oral liquidpreparations such as suspensions, syrups, elixirs, emulsions andsolutions; or solid carriers such as starches, sugars, kaolin, diluents,lubricants, binders, disintegrating agents and the like in the case ofpowders, pills, capsules, and tablets. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit forms, in which case solid pharmaceutical carriers areobviously employed. For parenteral compositions, the carrier willusually comprise sterile water, at least in large part, though otheringredients, for example, to aid solubility, may be included. Injectablesolutions, for example, may be prepared in which the carrier comprisessaline solution, glucose solution or a mixture of saline and glucosesolution. Injectable suspensions may also be prepared in which caseappropriate liquid carriers, suspending agents and the like may beemployed. Also included are solid form preparations which are intendedto be converted, shortly before use, to liquid form preparations. In thecompositions suitable for percutaneous administration, the carrieroptionally comprises a penetration enhancing agent and/or a suitablewetting agent, optionally combined with suitable additives of any naturein minor proportions, which additives do not introduce a significantdeleterious effect on the skin. Said additives may facilitate theadministration to the skin and/or may be helpful for preparing thedesired compositions. These compositions may be administered in variousways, e.g., as a transdermal patch, as a spot-on, as an ointment. Thecompounds of the present invention may also be administered viainhalation or insufflation by means of methods and formulations employedin the art for administration via this way. Thus, in general thecompounds of the present invention may be administered to the lungs inthe form of a solution, a suspension or a dry powder. Any systemdeveloped for the delivery of solutions, suspensions or dry powders viaoral or nasal inhalation or insufflation are suitable for theadministration of the present compounds.

To aid solubility of the compounds of formula (I), suitable ingredients,e.g. cyclodextrins, may be included in the compositions. Appropriatecyclodextrins are α-, β-, γ-cyclodextrins or ethers and mixed ethersthereof wherein one or more of the hydroxy groups of the anhydroglucoseunits of the cyclodextrin are substituted with C₁₋₆alkyl, particularlymethyl, ethyl or isopropyl, e.g. randomly methylated β-CD;hydroxyC₁₋₆alkyl, particularly hydroxyethyl, hydroxy-propyl orhydroxybutyl; carboxyC₁₋₆alkyl, particularly carboxymethyl orcarboxy-ethyl; C₁₋₆alkylcarbonyl, particularly acetyl. Especiallynoteworthy as complexants and/or solubilizers are β-CD, randomlymethylated β-CD, 2,6-dimethyl-β-CD, 2-hydroxyethyl-β-CD,2-hydroxyethyl-β-CD, 2-hydroxypropyl-β-CD and(2-carboxymethoxy)propyl-β-CD, and in particular 2-hydroxypropyl-β-CD(2-HP-β-CD).

The term mixed ether denotes cyclodextrin derivatives wherein at leasttwo cyclodextrin hydroxy groups are etherified with different groupssuch as, for example, hydroxy-propyl and hydroxyethyl.

The average molar substitution (M.S.) is used as a measure of theaverage number of moles of alkoxy units per mole of anhydroglucose. Theaverage substitution degree (D.S.) refers to the average number ofsubstituted hydroxyls per anhydroglucose unit. The M.S. and D.S. valuecan be determined by various analytical techniques such as nuclearmagnetic resonance (NMR), mass spectrometry (MS) and infraredspectroscopy (IR). Depending on the technique used, slightly differentvalues may be obtained for one given cyclodextrin derivative.Preferably, as measured by mass spectrometry, the M.S. ranges from 0.125to 10 and the D.S. ranges from 0.125 to 3.

Other suitable compositions for oral or rectal administration compriseparticles consisting of a solid dispersion comprising a compound offormula (I) and one or more appropriate pharmaceutically acceptablewater-soluble polymers.

The term “a solid dispersion” used hereinafter defines a system in asolid state (as opposed to a liquid or gaseous state) comprising atleast two components, in casu the compound of formula (I) and thewater-soluble polymer, wherein one component is dispersed more or lessevenly throughout the other component or components (in case additionalpharmaceutically acceptable formulating agents, generally known in theart, are included, such as plasticizers, preservatives and the like).When said dispersion of the components is such that the system ischemically and physically uniform or homogenous throughout or consistsof one phase as defined in thermo-dynamics, such a solid dispersion willbe called “a solid solution”. Solid solutions are preferred physicalsystems because the components therein are usually readily bioavailableto the organisms to which they are administered. This advantage canprobably be explained by the ease with which said solid solutions canform liquid solutions when contacted with a liquid medium such as thegastro-intestinal juices. The ease of dissolution may be attributed atleast in part to the fact that the energy required for dissolution ofthe components from a solid solution is less than that required for thedissolution of components from a crystalline or microcrystalline solidphase.

The term “a solid dispersion” also comprises dispersions which are lesshomogenous throughout than solid solutions. Such dispersions are notchemically and physically uniform throughout or comprise more than onephase. For example, the term “a solid dispersion” also relates to asystem having domains or small regions wherein amorphous,microcrystalline or crystalline compound of formula (I), or amorphous,microcrystalline or crystalline water-soluble polymer, or both, aredispersed more or less evenly in another phase comprising water-solublepolymer, or compound of formula (I), or a solid solution comprisingcompound of formula (I) and water-soluble polymer. Said domains areregions within the solid dispersion distinctively marked by somephysical feature, small in size, and evenly and randomly distributedthroughout the solid dispersion.

Various techniques exist for preparing solid dispersions includingmelt-extrusion, spray-drying and solution-evaporation.

The solution-evaporation process comprises the following steps:

-   a) dissolving the compound of formula (I) and the water-soluble    polymer in an appropriate solvent, optionally at elevated    temperatures;-   b) heating the solution resulting under point a), optionally under    vacuum, until the solvent is evaporated. The solution may also be    poured onto a large surface so as to form a thin film, and    evaporating the solvent therefrom.

In the spray-drying technique, the two components are also dissolved inan appropriate solvent and the resulting solution is then sprayedthrough the nozzle of a spray dryer followed by evaporating the solventfrom the resulting droplets at elevated temperatures.

The preferred technique for preparing solid dispersions is themelt-extrusion process comprising the following steps:

-   -   a) mixing a compound of formula (I) and an appropriate        water-soluble polymer,    -   b) optionally blending additives with the thus obtained mixture,    -   c) heating and compounding the thus obtained blend until one        obtains a homogenous melt,    -   d) forcing the thus obtained melt through one or more nozzles;        and    -   e) cooling the melt till it solidifies.

The terms “melt” and “melting” should be interpreted broadly. Theseterms not only mean the alteration from a solid state to a liquid state,but can also refer to a transition to a glassy state or a rubbery state,and in which it is possible for one component of the mixture to getembedded more or less homogeneously into the other. In particular cases,one component will melt and the other component(s) will dissolve in themelt thus forming a solution, which upon cooling may form a solidsolution having advantageous dissolution properties.

After preparing the solid dispersions as described hereinabove, theobtained products can be optionally milled and sieved.

The solid dispersion product may be milled or ground to particles havinga particle size of less than 600 μm, preferably less than 400 μm andmost preferably less than 125 μm.

The particles prepared as described hereinabove can then be formulatedby conventional techniques into pharmaceutical dosage forms such astablets and capsules.

It will be appreciated that a person of skill in the art will be able tooptimize the parameters of the solid dispersion preparation techniquesdescribed above, such as the most appropriate solvent, the workingtemperature, the kind of apparatus being used, the rate of spray-drying,the throughput rate in the melt-extruder

The water-soluble polymers in the particles are polymers that have anapparent viscosity, when dissolved at 20° C. in an aqueous solution at2% (w/v), of 1 to 5000 mPa·s more preferably of 1 to 700 mPa·s, and mostpreferred of 1 to 100 mPa·s. For example, suitable water-solublepolymers include alkylcelluloses, hydroxyalkylcelluloses, hydroxyalkylalkylcelluloses, carboxyalkylcelluloses, alkali metal salts ofcarboxyalkylcelluloses, carboxyalkylalkylcelluloses,carboxyalkylcellulose esters, starches, pectines, chitin derivates, di-,oligo- and polysaccharides such as trehalose, alginic acid or alkalimetal and ammonium salts thereof, carrageenans, galactomannans,tragacanth, agar-agar, gummi arabicum, guar gummi and xanthan gummi,polyacrylic acids and the salts thereof, polymethacrylic acids and thesalts thereof, methacrylate copolymers, polyvinylalcohol,polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinylacetate, combinations of polyvinylalcohol and polyvinylpyrrolidone,polyalkylene oxides and copolymers of ethylene oxide and propyleneoxide. Preferred water-soluble polymers are hydroxypropylmethylcelluloses.

Also one or more cyclodextrins can be used as water soluble polymer inthe preparation of the above-mentioned particles as is disclosed in WO97/18839. Said cyclodextrins include the pharmaceutically acceptableunsubstituted and substituted cyclodextrins known in the art, moreparticularly α, β or γ cyclodextrins or the pharmaceutically acceptablederivatives thereof.

Substituted cyclodextrins which can be used to prepare the abovedescribed particles include polyethers described in U.S. Pat. No.3,459,731. Further substituted cyclodextrins are ethers wherein thehydrogen of one or more cyclodextrin hydroxy groups is replaced byC₁₋₆alkyl, hydroxyC₁₋₆alkyl, carboxy-C₁₋₆alkyl orC₁₋₆alkyloxycarbonylC₁₋₆alkyl or mixed ethers thereof. In particularsuch substituted cyclodextrins are ethers wherein the hydrogen of one ormore cyclodextrin hydroxy groups is replaced by C₁₋₃alkyl,hydroxyC₂₋₄alkyl or carboxyC₁₋₂alkyl or more in particular by methyl,ethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, carboxymethyl orcarboxyethyl.

Of particular utility are the β-cyclodextrin ethers, e.g.dimethyl-β-cyclodextrin as described in Drugs of the Future, Vol. 9, No.8, p. 577-578 by M. Nogradi (1984) and polyethers, e.g. hydroxypropylβ-cyclodextrin and hydroxyethyl β-cyclodextrin, being examples. Such analkyl ether may be a methyl ether with a degree of substitution of about0.125 to 3, e.g. about 0.3 to 2. Such a hydroxypropyl cyclodextrin mayfor example be formed from the reaction between β-cyclodextrin anpropylene oxide and may have a MS value of about 0.125 to 10, e.g. about0.3 to 3.

Another type of substituted cyclodextrins is sulfobutylcyclodextrines.

The ratio of the compound of formula (I) over the water soluble polymermay vary widely. For example ratios of 1/100 to 100/1 may be applied.Interesting ratios of the compound of formula (I) over cyclodextrinrange from about 1/10 to 10/1. More interesting ratios range from about1/5 to 5/1.

It may further be convenient to formulate the compounds of formula (I)in the form of nanoparticles which have a surface modifier adsorbed onthe surface thereof in an amount sufficient to maintain an effectiveaverage particle size of less than 1000 nm. Useful surface modifiers arebelieved to include those which physically adhere to the surface of thecompound of formula (I) but do not chemically bond to said compound.

Suitable surface modifiers can preferably be selected from known organicand inorganic pharmaceutical excipients. Such excipients include variouspolymers, low molecular weight oligomers, natural products andsurfactants. Preferred surface modifiers include nonionic and anionicsurfactants.

Yet another interesting way of formulating the compounds of formula (I)involves a pharmaceutical composition whereby the compounds of formula(I) are incorporated in hydrophilic polymers and applying this mixtureas a coat film over many small beads, thus yielding a composition whichcan conveniently be manufactured and which is suitable for preparingpharmaceutical dosage forms for oral administration.

Said beads comprise a central, rounded or spherical core, a coating filmof a hydrophilic polymer and a compound of formula (I) and optionally aseal-coating layer.

Materials suitable for use as cores in the beads are manifold, providedthat said materials are pharmaceutically acceptable and have appropriatedimensions and firmness. Examples of such materials are polymers,inorganic substances, organic substances, and saccharides andderivatives thereof.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in unit dosage form for ease ofadministration and uniformity of dosage. Unit dosage form as used hereinrefers to physically discrete units suitable as unitary dosages, eachunit containing a predetermined quantity of active ingredient calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. Examples of such unit dosage forms aretablets (including scored or coated tablets), capsules, pills, powderpackets, wafers, suppositories, injectable solutions or suspensions andthe like, and segregated multiples thereof.

Those of skill in the treatment of HIV-infection could determine theeffective daily amount from the test results presented here. In generalit is contemplated that an effective daily amount would be from 0.01mg/kg to 50 mg/kg body weight, more preferably from 0.1 mg/kg to 10mg/kg body weight. It may be appropriate to administer the required doseas two, three, four or more sub-doses at appropriate intervalsthroughout the day. Said sub-doses may be formulated as unit dosageforms, for example, containing 1 to 1000 mg, and in particular 5 to 200mg of active ingredient per unit dosage form.

The exact dosage and frequency of administration depends on theparticular compound of formula (I) used, the particular condition beingtreated, the severity of the condition being treated, the age, weightand general physical condition of the particular patient as well asother medication the individual may be taking, as is well known to thoseskilled in the art. Furthermore, it is evident that said effective dailyamount may be lowered or increased depending on the response of thetreated subject and/or depending on the evaluation of the physicianprescribing the compounds of the instant invention. The effective dailyamount ranges mentioned hereinabove are therefore only guidelines andare not intended to limit the scope or use of the invention to anyextent.

The present compounds of formula (I) can be used alone or in combinationwith other therapeutic agents, such as anti-virals, antibiotics,immunomodulators or vaccines for the treatment of viral infections. Theymay also be used alone or in combination with other prophylactic agentsfor the prevention of viral infections. The present compounds may beused in vaccines and methods for protecting individuals against viralinfections over an extended period of time. The compounds may beemployed in such vaccines either alone or together with other compoundsof this invention or together with other anti-viral agents in a mannerconsistent with the conventional utilization of reverse transcriptaseinhibitors in vaccines. Thus, the present compounds may be combined withpharmaceutically acceptable adjuvants conventionally employed invaccines and administered in prophylactically effective amounts toprotect individuals over an extended period of time against HIVinfection.

Also, the combination of an antiretroviral compound and a compound offormula (I) can be used as a medicine. Thus, the present invention alsorelates to a product containing (a) a compound of formula (I), and (b)another antiretroviral compound, as a combined preparation forsimultaneous, separate or sequential use in anti-HIV treatment. Thedifferent drugs may be combined in a single preparation together withpharmaceutically acceptable carriers. Said other antiretroviralcompounds may be known antiretroviral compounds such as suramine,pentamidine, thymopentin, castanospermine, dextran (dextran sulfate),foscarnet-sodium (trisodium phosphono formate); nucleoside reversetranscriptase inhibitors, e.g. zidovudine (3′-azido-3′-deoxythymidine,AZT), didanosine (2′,3′-dideoxyinosine; ddI), zalcitabine(dideoxycytidine, ddC) or lamivudine (2′-3′-dideoxy-3′-thiacytidine,3TC), stavudine (2′,3′-didehydro-3′-deoxythymidine, d4T), abacavir andthe like; non-nucleoside reverse transcriptase inhibitors such asnevirapine (11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido-[

3,2-b:2′,3′-e][1,4]diazepin-6-one), efavirenz, delavirdine, TMC-120,TMC-125 and the like; phosphonate reverse transcriptase inhibitors, e.g.tenofovir and the like; compounds of the TIBO(tetrahydro-imidazo[4,5,1-jk][1,4]-benzodiazepine-2(1H)-one andthione)-type e.g.(S)-8-chloro-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)-imidazo-[4,5,1-jk][1,4]benzodiazepine-2(1H)-thione;compounds of the α-APA (α-anilino phenyl acetamide) type e.g.α-[(2-nitrophenyl)amino]-2,6-di-chlorobenzene-acetamide and the like;inhibitors of trans-activating proteins, such as TAT-inhibitors, e.g.RO-5-3335, or REV inhibitors, and the like; protease inhibitors e.g.indinavir, ritonavir, saquinavir, lopinavir (ABT-378), nelfinavir,amprenavir, TMC-126, BMS-232632, VX-175 and the like; fusion inhibitors,e.g. T-20, T-1249 and the like; CXCR4 receptor antagonists, e.g.AMD-3100 and the like; inhibitors of the viral integrase;nucleotide-like reverse transcriptase inhibitors, e.g. tenofovir and thelike; ribonucleotide reductase inhibitors, e.g. hydroxyurea and thelike.

By administering the compounds of the present invention with otheranti-viral agents which target different events in the viral life cycle,the therapeutic effect of these compounds can be potentiated.Combination therapies as described above exert a synergistic effect ininhibiting HIV replication because each component of the combinationacts on a different site of HIV replication. The use of suchcombinations may reduce the dosage of a given conventionalanti-retroviral agent which would be required for a desired therapeuticor prophylactic effect as compared to when that agent is administered asa monotherapy. These combinations may reduce or eliminate the sideeffects of conventional single anti-retroviral therapy while notinterfering with the anti-viral activity of the agents. Thesecombinations reduce potential of resistance to single agent therapies,while minimizing any associated toxicity. These combinations may alsoincrease the efficacy of the conventional agent without increasing theassociated toxicity.

The compounds of the present invention may also be administered incombination with immunomodulating agents, e.g. levamisole, bropirimine,anti-human alpha interferon antibody, interferon alpha, interleukin 2,methionine enkephalin, diethyldithiocarbamate, tumor necrosis factor,naltrexone and the like; antibiotics, e.g. pentamidine isethiorate andthe like; cholinergic agents, e.g. tacrine, rivastigmine, donepezil,galantamine and the like; NMDA channel blockers, e.g. memantine toprevent or combat infection and diseases or symptoms of diseasesassociated with HIV infections, such as AIDS and ARC, e.g. dementia. Acompound of formula (I) can also be combined with another compound offormula (I).

Although the present invention focuses on the use of the presentcompounds for preventing or treating HIV infections, the presentcompounds may also be used as inhibitory agents for other viruses whichdepend on similar reverse transcriptases for obligatory events in theirlife cycle.

The following examples are intended to illustrate the present invention.

EXPERIMENTAL PART

Hereinafter, “DMF” is defined as N,N-dimethylformamide, “DIPE” isdefined as diisopropyl ether, “THF” is defined as tetrahydrofurane,“DMA” is defined as N,N-dimethylacetamide, “DMSO” is defined asdimethylsulfoxide, “DME” is defined as dimethyl ether, “EtOAc” isdefined as ethylacetate, “EDCI” is defined asN′-(ethylcarbonimidoyl)-N,N-dimethyl-1,3-propanediamine.

A. Preparation of the Intermediate Compounds Example A1

a) The Preparation of Intermediate 1

nBuLi (0.012 mol) was added dropwise at −70° C. to a mixture ofN′-(4-bromo-2,6-dimethylphenyl)-N,N-dimethylmethanimidamide (0.0078 mol)in THF (20 ml) under N₂ flow. The mixture was stirred at −30° C. for 30minutes, then cooled to −70° C. A mixture of DMF (0.078 mol) in THF (30ml) was added dropwise. The mixture was stirred at−70° C. for 2 hours, then brought to 0° C., poured out into H₂O andextracted with ethyl acetate. The organic layer was separated, dried(MgSO₄), filtered and the solvent was evaporated. Yield: 1.8 g ofintermediate 1.b) The Preparation of Intermediate 2

A mixture of diethyl (cyanomethyl)phosphonate (0.0037 mol) in THF (10ml) was cooled to 5° C. under N₂ flow. Potassium tert.-butoxide (0.0037mol) was added portionwise. The mixture was stirred at 5° C. for 30minutes, then stirred at room temperature for 30 minutes. A mixture ofintermediate 1 (0.0024 mol) in THF (10 ml) was added. The mixture wasstirred at room temperature for 1 hour, then poured out into H₂O andextracted with CH₂Cl₂. The organic layer was separated, dried (MgSO₄),filtered and the solvent was evaporated. Yield: 0.82 g (100%) ofintermediate 2.

c) The Preparation of Intermediate 3 and Intermediate 22

A mixture of intermediate 2 (0.059 mol) and ZnCl₂ (0.299 mol) in ethanol(150 ml) was stirred and refluxed for 24 hours, then poured out intoK₂CO₃ solution (10% in water) and extracted with CH₂Cl₂. The organiclayer was separated, dried (MgSO₄), filtered and the solvent wasevaporated. The residue (9 g) was crystallized from DIPE. Theprecipitate was filtered off and dried. Yield: 0.8 g (6%) ofintermediate 22. The filtrate was concentrated and recrystallized fromDIPE to obtain 6 g of intermediate 3.

Alternatively, intermediate 3 was also prepared as follows:

To a solution of 159 g of 4-iodo-2,6-dimethyl-benzenamine was added 63.8g of sodium acetate. The reaction mixture was kept under nitrogenatmosphere. 7 g of moistered palladium on charcoal (Pd/C 10%) and 64.4ml of acrylonitrile was added. The reaction mixture was heated to 130°C. and stirred overnight. After cooling to room temperature, 0.5 l oftoluene and 0.5 l of N,N-dimethylacetamide was added. The reactionmixture was filtered over Dicalite and the filter was washed with 0.5 lof toluene. Water (6 l) was added to the mixture which was stirred for30 minutes. The layers were separated. To the aqueous layer, 1 l oftoluene was added and the mixture was stirred for 30 minutes. The layerswere separated again. The separated organic layers were collected andthe solvent was evaporated, yielding 123 g of intermediate 3.

Intermediate 3 was converted into its hydrochloric acid salt as follows:

To a mixture of 123 g of intermediate 3 in 630 ml of ethanol was added1.25 l of diisopropyl ether. The reaction mixture was kept undernitrogen atmosphere. The mixture was heated to 60° C. and stirred for 30minutes. 120 ml of a 6 N solution of hydrochloric acid in 2-propanol wasadded and the mixture was stirred for 30 minutes. After cooling to roomtemperature, the reaction mixture was filtered and the residue waswashed with 100 ml of 2-propanol. The resulting residue was dried underreduced pressure at 50° C. Yield: 103 g (77%) of the hydrochloric acidsalt (1:1) of intermediate 3.

Intermediate 3 (E) was Prepared as Follows

x) Preparation of Intermediate 3a (E)

In 10 ml acetonitrile, dry, was dissolved 2.00 g (10.0 mol) of4-bromo-2,6-dimethylaniline, 1.07 g (1.5 eq) of acrylamide, 224 mg (0.1eq) of Pd(OAc)₂, 609 mg (0.2 eq) of tris(2-methylphenyl)phosphine and1.52 g of N,N-diethylethanamine. The mixture was purged with N₂ for 20minutes and stirred overnight at 70° C. The mixture was diluted with 150ml of methylene chloride, washed with saturated aqueous NaHCO₃ solution,dried (sat. NaCl, Na₂SO₄) and filtered. The solvent was evaporated andthe residue was stirred in diisopropyl ether followed by filtration.Yield: 1.51 g (79.5%) of intermediate 3a (E).

y) Preparation of Intermediate 3 (E)

POCl₃ (3 ml) was cooled to 0° C. and 500 mg (2.63 mmol) of intermediate3a (E) was added. After 30 minutes, the cooling bath was removed and themixture was stirred overnight at 20° C. The mixture was added dropwiseto 150 ml of diisopropyl ether while stirring vigorously. Theprecipitate was filtered and washed with diisopropyl ether. The residuewas added to 100 ml ethyl acetate/100 ml of saturated aqueous NaHCO₃solution and stirred. The ethyl acetate layer was separated, dried (sat.NaCl, Na₂SO₄) and filtered. The solvent was evaporated. Yield: 380 mg(84%) of intermediate 3 (E).

d) The Preparation of Intermediate 4

A mixture of 4-bromo-2,6-dimethylbenzenamine (0.024 mol) in H₂SO₄ (30ml) was stirred at −5° C. KNO₃ (0.024 mol) was added slowly. The mixturewas stirred at −5° C. for 30 minutes, poured out into H₂O and extractedwith ethyl acetate. The organic layer was washed with H₂O, separated,dried (MgSO₄), filtered and the solvent was evaporated. The residue(0.058 g, 95%) was purified by column chromatography over silica gel(eluent: cyclohexane/ethyl acetate; 70/30; 15-40 μm). The pure fractionswere collected and the solvent was evaporated. Yield: 4.1 g ofintermediate 4.

Example A1A

The Preparation of Intermediate 28

1-chloro-pyrrolidine-2,5-dione (0.032 mol) was added at 60° C. to amixture of 4-amino-3-methyl-benzoic acid ethyl ester [CAS 40800-65-5](0.029 mol) in CH₃CN (50 ml). The mixture was stirred and refluxedslowly. K₂CO₃ 10% was added. The mixture was extracted with CH₂Cl₂. Theorganic layer was evaporated. The residue (6.6 g) was purified by columnchromatography over silica gel (eluent: cyclohexane/EtOAc 85/15; 15-40μm). The pure fractions were collected and the solvent was evaporated.Yield: 5.2 g of intermediate 28 (84%).

Example A2

A mixture of 4-[(1,4-dihydro-4-oxo-2-pyrimidinyl)amino]benzonitrile(0.12 mol) in POCl₃ (90 ml) was stirred and refluxed under Argon for 20minutes. The reaction mixture was slowly poured onto 750 ml ice/water,and the solid was separated by filtration. The solid was suspended in500 ml water, and the pH of the suspension was adjusted to neutral byadding a 20% NaOH solution. The solid was again separated by filtration,suspended in 200 ml 2-propanone, and 1000 ml CH₂Cl₂ was added. Themixture was heated until all solid had dissolved. After cooling to roomtemperature, the aqueous layer was separated, and the organic layer wasdried. During removal of the drying agent by filtration, a white solidformed in the filtrate. Further cooling of the filtrate in the freezer,followed by filtration, yielded 21.38 g (77.2%) of[4-[(4-chloro-2-pyrimidinyl)amino]benzonitrile (interm. 5).

Example A3

a) The Preparation of Intermediate 6

nBuLi (0.024 mol) was added dropwise at −70° C. to a mixture ofN′-(4-bromo-2,6-dimethylphenyl)-N,N-dimethylmethanimidamide (0.0157 mol)in THF (50 ml) under N₂ flow. The mixture was stirred at −30° C. for 30minutes, then cooled to −70° C. A solution of 2-methylpropanal (0.055mol) in THF (50 ml) was added. The mixture was stirred at

−70° C. for 2 hours, then brought to 0° C., poured out into H₂O andextracted with CH₂Cl₂. The organic layer was separated, dried (MgSO₄),filtered and the solvent was evaporated. The residue (6.7 g) waspurified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH/NH₄OH 95/5/0.5; 15-40 μm). Two fractions were collected andthe solvent was evaporated. Fraction 1: yield: 1.5 g of intermediate 6(38%).b) The Preparation of Intermediate 7

Tris[2-(2-methoxyethoxy)ethyl]amine (0.0193 mol) was added at roomtemperature to a solution of intermediate 6 (0.0048 mol) in CH₂Cl₂ (20ml). KMnO₄ (0.0193 mol) was added portionwise. The mixture was stirredat room temperature overnight, then filtered over celite and washed withCH₂Cl₂. The organic layer was washed with K₂CO₃ 10%, separated, dried(MgSO₄), filtered and the solvent was evaporated. Yield: 1.2 g (100%) ofintermediate 7.

c) The Preparation of Intermediate 8

A mixture of intermediate 7 (0.0043 mol) and ZnCl₂ (0.017 mol) inethanol (20 ml) was stirred and refluxed overnight, poured out into H₂Oand extracted with CH₂Cl₂/CH₃OH.

The organic layer was separated, dried (MgSO₄), filtered and the solventwas evaporated. Yield: 0.94 g (82%) of intermediate 8.

d-1) The Preparation of Intermediate 9

A mixture of intermediate 8 (0.0049 mol) and intermediate 5 (0.0025 mol)was stirred at 150° C. for 2 hours and taken up in K₂CO₃10%/CH₂Cl₂/CH₃OH. The organic layer was separated, dried (MgSO₄),filtered and the solvent was evaporated. The residue (1.3 g) wascrystallized from DIPE. The precipitate was filtered off and dried. Themother layer was purified by column chromatography over silica gel(eluent: CH₂Cl₂/CH₃OH 98.5/1.5; 15-40 μm). The pure fractions werecollected and the solvent was evaporated. Yield: 0.21 g of intermediate9.

d-2) The Preparation of Intermediate 29

A mixture of intermediate 28 (0.023 mol) and intermediate 5 (preparedaccording to A2) (0.025 mol) in HCl 3N (10 ml) was stirred at 105° C.then brought to room temperature and filtered. The precipitate waswashed with DIPE and dried. Yield: 8.4 g of intermediate 29 (96%)

d-3) The Preparation of Intermediate 30

A mixture of 4-amino-3-chloro benzoic acid ethyl ester [CAS 82765-44-4](0.02 mol) and intermediate 5 (prepared according to A2) (0.0243 mol) in1-methyl-pyrrolidin-2-one (40 ml) was stirred at 180° C. for 2 hours,then poured out into H₂O and extracted three times with EtOac (80 ml).The organic layer was separated, dried (MgSO₄), filtered and the solventwas evaporated. The residue (10 g) was purified by column chromatographyover silica gel (eluent: CH₂Cl₂ 100; 15-30 μm). Two fractions werecollected and the solvent was evaporated. Yield: 1.7 g F1 and 1 g F2. F2was taken up in diethyl ether. The precipitate was filtered off anddried. Yield: 0.95 g of intermediate 30 (12%).

e-1) The Preparation of Intermediate 17

NaBH₄ (0.0001 mol) was added portionwise at 5° C. to a mixture ofintermediate 9 (0.0001 mol) in ethanol (7 ml) under N₂ flow. The mixturewas stirred at 5° C. for 1 hour, poured out on ice and extracted withCH₂Cl₂. The organic layer was separated, dried (MgSO₄), filtered, andthe solvent was evaporated. The residue (0.1 g) was crystallized fromDIPE. The precipitate was filtered off and dried. Yield: 0.044 g ofintermediate 17.

e-2) The Preparation of Intermediate 32

BuLi 1.6 M (0.009 mol) was added at −78° C. to a mixture of

(intermediate 31) (prepared according to A4a) (0.0029 mol) in THF (25ml) under N₂ flow. The mixture was stirred at −78° C. for 10 minutes,then brought to room temperature and stirred for 3 hours. H₂O was added.The mixture was extracted with CH₂Cl₂. The organic layer was separated,dried (MgSO₄), filtered, and the solvent was evaporated. The residue(1.28 g) was purified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH/NH₄OH 98/2/0.1; 15-40 μm). Three fractions were collectedand the solvent was evaporated. Yield: 0.189 g of fraction 1, 0.14 g offraction 2 and 0.5 g of fraction 3 (48%). Fraction 3 was purified bycolumn chromatography over kromasil (eluent: CH₂Cl₂/EtOAc 80/20; 10 μm).Two fractions (F1, F2) were collected and the solvent was evaporated.Yield: 0.25 g F1 (24%) and 0.1 g of F2. F1 was crystallized from diethylether. The precipitate was filtered off and dried. Yield: 0.21 g ofintermediate 32 (20%).e-3) The Preparation of Intermediate 34

A solution of methylmagnesium iodide (1.0M solution in diethylether)(0.6 ml) was added to a solution of

intermediate 33 (prepared according to A5.a) (0.0006 mol) in THF (3 ml).The mixture was stirred for 2 hours. H₂O was added. The mixture wasfiltered over celite. H₂O was added. The mixture was extracted withEtOAc. The organic layer was separated, dried (MgSO₄), filtered, and thesolvent was evaporated. The residue (0.05 g) was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH 96/4; 15-40 μm).The pure fractions were collected and the solvent was evaporated. Yield:0.015 g of intermediate 34 (7.2%).

Example A4

a) The Preparation of Intermediate 10

A mixture of ethyl 3,5-dimethyl-4-hydroxy benzoate (0.0025 mol) in1,4-dioxane (2.5 ml) was stirred at room temperature under N₂ flow.Sodium hydride (0.0033 mol) was added. The mixture was stirred for 2minutes. Intermediate 5 (0.0028 mol) was added. The mixture was stirredfor 10 minutes. 1-methyl-2-pyrrolidinone (2.5 ml) was added. The mixturewas stirred at 150° C. for 12 hours, poured out into H₂O and extractedwith CH₂Cl₂/CH₃OH. The organic layer was separated, dried (MgSO₄),filtered and the solvent was evaporated. The residue (1.7 g) waspurified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH92/8; 15-40 μm). The pure fractions were collected and the solvent wasevaporated. Yield: 0.7 g of intermediate 10 (70%).

b-1) The Preparation of Intermediate 11

A solution of intermediate 10 (0.0005 mol) in THF (5 ml) was addeddropwise at 0° C. to a suspension of LiAlH₄ (0.001 mol) in THF (5 ml)under N₂ flow. The mixture was stirred at 0° C. for 1 hour and pouredout into H₂O (0.5 ml). CH₂Cl₂ was added. The organic layer wasseparated, dried (MgSO₄), filtered, and the solvent was evaporated. Theresidue was purified by column chromatography over kromasil (eluent:CH₂Cl₂ 100 to CH₂Cl₂/CH₃OH 99/1; 5 μm). The pure fractions werecollected and the solvent was evaporated. The residue (0.1 g) wascrystallized from diethyl ether. The precipitate was filtered off anddried. Yield: 0.043 g of intermediate 11 (24%).

b-2) The Preparation of Intermediate 37

LiAlH₄ (0.0196 mol, 0.75 g) was added portionwise at 5° C. to a mixtureof intermediate 29 (prepared according to A3d-2) (0.0098 mol) in THF(100 ml) under N₂ flow. The mixture was stirred at room temperatureovernight, poured out into EtOAc, then into H₂O and filtered overcelite. The organic layer was separated, dried (MgSO₄), filtered, andthe solvent was evaporated. Yield: 3.4 g. This fraction was purified bycolumn chromatography over kromasil (eluent: CH₂Cl₂/CH₃OH/NH₄OH97/3/0.1; 15-40 μm). The pure fractions were collected and the solventwas evaporated. Yield 1 g (27%). This fraction was crystallized fromDIPE/CH₃CN. The precipitate was filtered off and dried. Yield: 0.03 g ofintermediate 37.

c) The Preparation of Intermediate 12

A mixture of intermediate 11 (0.0043 mol) in CH₂Cl₂ (50 ml) was stirredat 0° C. SOCl₂ (0.0206 mol) was added dropwise. The mixture was pouredout into ice water/K₂CO₃. The mixture was stirred at room temperaturefor 5 minutes. The organic layer was separated, dried (MgSO₄), filtered,and the solvent was evaporated. Yield: 1.5 g of intermediate 12 (98%).

d) The Preparation of Intermediate 55

Jones's reagent (0.0084 mol) was added to a mixture of intermediate 19(see Table 1) (prepared according to A4b-1) (0.0028 mol) in acetone (50ml). The mixture was stirred at room temperature for 2 hours then pouredout into H₂O and basified with NaHCO₃. The precipitate was filtered offand dried. Yield: 1.39 g. The residue (0.1 g) was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 85/15/1 thenCH₃OH 100). The pure fraction was crystallized from isopropanol/DIPE.Yield: 0.071 g of intermediate 55.

Example A5

a) The Preparation of Intermediate 13

A mixture of intermediate 19 (see Table 1) (prepared according toA4.b-1) (0.0037 mol) and MnO₂ (0.0185 mol) in CH₂Cl₂ (100 ml) wasstirred at room temperature overnight, then filtered over celite. Thefiltrate was evaporated. Yield: 1.3 g of intermediate 13.

b) The Preparation of Intermediate 21

A mixture of intermediate 13 (prepared according to A5.a) (0.0029 mol)and H₂N—NH₂, H₂O (0.0058 mol) in EtOH (10 ml) was stirred at roomtemperature overnight. The solvent was evaporated till dryness. Yield:0.53 g of intermediate 21.

Example A6

The Preparation of Intermediate 14

Hydrazine (0.0077 mol) was added to a mixture of

(prepared according to A3.d-1) (0.0005 mol) in EtOH (10 ml). The mixturewas stirred and refluxed overnight. Hydrazine (0.028 mol) was added. Themixture was stirred and refluxed overnight. Yield: 0.28 g ofintermediate 14.

Example A7

a) The Preparation of Intermediate 23

A mixture of intermediate 35

(prepared according to A3.d-1) (0.0056 mol) in HCl 3N (60 ml) and iPrOH(15 ml) was stirred and refluxed overnight. The precipitate wasfiltered, washed with H₂O, taken up in DIPE and dried. Yield: 2.3 g ofintermediate 23 (100%).b) The Preparation of Intermediate 56

A mixture of intermediate 10 (prepared according to A4.a) (0.0012 mol)in HCl 3N (26 ml) and iPrOH (4 ml) was stirred and refluxed for 12hours. The solvent was evaporated till dryness. The residue was taken upin (CH₃)₂CO. The solvent was evaporated. The residue was taken up indiethyl ether. The precipitate was filtered off and dried. Yield: 0.4 g(78.5%). This fraction was stirred at 60° C. for 20 minutes.

Yield: 0.19 g. This fraction was crystallized from H₂O/2-propanone. Theprecipitate was filtered off and dried. Yield: 0.12 g of intermediate 56(26%).

Example A8

a) The Preparation of Intermediate 24

A mixture of intermediate 31 (prepared according to A4.a) (0.0005 mol)and (triphenylphosphoranylidene)acetic acid ethyl ester [CAS1099-45-2](0.0006 mol in THF (5 ml) was stirred at 80° C. for 48 hours, poured outinto H₂O and extracted with CH₂Cl₂. The organic layer was separated,dried (MgSO₄), filtered and the solvent was evaporated. The residue (0.4g) was crystallized from DIPE. The precipitate was filtered off anddried. Yield: 0.08 g (33%). This fraction was crystallized fromDIPE/CH₃CN. The precipitate was filtered off and dried. Yield:intermediate 24 (33%).

b) The Preparation of Intermediate 25

Piperidine (0.0011 mol) was added at room temperature for 30 minutes.Intermediate 31 (prepared according to A4.a) (0.0005 mol) was added. Themixture was stirred at room temperature for 1 hour, poured out into H₂Oand extracted with CH₂Cl₂. The precipitate was filtered off and dried.The residue (0.2 g) was crystallized from CH₃CN/DIPE. The precipitatewas filtered off and dried. Yield: 0.048 g of intermediate 25 (19%) (mp.222° C.).

Example A9

The Preparation of Intermediate 26

A mixture of

(prepared according to A3.d-1) (0.0011 mol) and Pd/C (0.2 g) in methanol(30 ml) was hydrogenated at room temperature for 2 hours under one barpressure, then filtered over celite. Celite was washed with CH₃OH. Thefiltrate was evaporated till dryness. The residue (0.3 g) wascrystallized from 2-propanone/CH₃OH/diethyl ether. The precipitate wasfiltered off and dried. Yield: 0.07 g of fraction 1. Fraction 1 waspurified by column chromatography over kromasyl (eluent: CH₂Cl₂/CH₃OH99.5/0.5; 5 μm). Three fractions 9F1, F2, F3) were collected and thesolvent was evaporated. Yield: 0.0516 g F1, 0.1 g F2 and 0.15 g F3. F1was taken up in diethyl ether. The precipitate was filtered off anddried. Yield: 0.028 g of intermediate 26 (8%) (mp. 272° C.).

Example A10

The Preparation of Intermediate 27

A mixture of

(prepared according to A4.c) (0.0005 mol) andtriphenylphosphine (0.0005 mol) in CH₃CN (10 ml) was stirred andrefluxed for a week end. The solvent was evaporated till dryness. Theresidue was taken up in diethyl ether. The precipitate was filtered offand dried. Yield: 0.34 g of intermediate 27 (94%).

Example A11

The Preparation of Intermediate 58

A mixture of 4-bromo-2,6-dimethylbenzenamine (0.013 mol) andintermediate 5 (0.013 mol) was stirred at 150° C. for 1 hour. Themixture was poured into K₂CO₃ 10% aqueous solution and extracted withCH₂Cl₂/MeOH (95/5). The organic layer was separated, dried (MgSO₄),filtered and the solvent was evaporated. The residue was crystallizedfrom diisopropyl ether. The precipitate was filtered off and dried.Yield: 2.3 g (45%). The mother layer was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH—NH₄OH 98.5/1.5;15-40 μm). The pure fractions were collected and the solvent wasevaporated. Yield: 0.90 g (17%). The global yield of intermediate 5 was:3.2 g (62%).

Intermediate 59 was Prepared Analogously

Table 1 and 2 list intermediates which intervene in the preparation ofcompounds of the present invention.

TABLE 1

Interm. No. Ex. No. X₁ R³ R^(4a) R^(4b) Physical data 11 A4b-1 O —CH₂—OHCH₃ CH₃ 12 A4c O —CH₂—Cl CH₃ CH₃ 16 A3e NH —CH(OH)—CH₃ CH₃ CH₃ 17 A3e NH—CH(OH)—CH(CH₃)₂ CH₃ CH₃ 18 A3e NH —CH(OH)—CH₂—CH₃ CH₃ CH₃ 19 A4b-1 NH—CH₂—OH CH₃ CH₃ 15 A4c NH —CH₂—Cl CH₃ CH₃ 24 A8a O —CH═CH—C(═O)—O—C₂H₅CH₃ CH₃ mp. 180° C.; (E) 25 A8b O

CH₃ CH₃ mp. 222° C.; (A) 35 A3d-1 NH —CH═CH—C(═O)—O—C₂H₅ CH₃ CH₃ mp.200° C.; (E) 23 A7a NH —CH═CH—COOH CH₃ CH₃ 34 A3e-3 NH —CH(OH)—CH₃ CH₃ Hmp. 182° C. 36 A4b-1 NH —CH₂—OH CH₃ H mp. 210° C. 37 A4b-2 NH —CH₂—OH ClCH₃ 38 A4b-1 NH —CH₂—OH Cl H mp. 226° C. 39 A3e-1 O —CH(OH)—CH₃ CH₃ Hmp. 160° C. 40 A4b-1 S —CH₂—OH CH₃ CH₃ mp. 173° C. 41 A4b-1 NH —CH₂—OHBr H mp. 234° C. 32 A3e-2 O —CH(OH)—CH₃ CH₃ CH₃ mp. 193° C. 42 A4b-1 NH—CH₂—OH Br CH₃ mp. 250° C. 43 A4b-1 NH —CH₂—OH OH H mp. 124° C. 44 A4b-1NH —CH₂—OH H H mp. 215° C. 45 A4b-1 NH —CH₂—OH O—CH₃ H 46 A4b-1 NH—CH₂—OH CF₃ H mp. 194° C. 47 A4c NH —CH₂—Cl Cl CH₃ 48 A4c NH —CH₂—Cl ClH 49 A3e-1 O —CH₂—OH CH₃ H 50 A4c O —CH₂—Cl CH₃ H 51 A4b-1 NH —CH₂—OHC(CH₃)₃ H 52 A4c NH —CH₂—Cl CH₃ H 53 A4b-1 NH —CH₂—OH 2-furanyl CH₃ 54A4c NH —CH₂—Cl Br CH₃ 57 A7b O —CH═CH—COOH CH₃ CH₃

TABLE 2

Interm. No. Ex. No. X₁ R³ Physical data 20 A3e NH —CHOH—CH₃

B. Preparation of the Final Compounds Example B1

The Preparation of Compound 1

A mixture of intermediate 3 (0.034 mol) and intermediate 5 (0.0174 mol)was stirred at 150° C. for 1 hour and taken up in K₂CO₃10%/CH₂Cl₂/CH₃OH. The organic layer was separated, dried (MgSO₄),filtered, and the solvent was evaporated. The residue (10 g) waspurified by column chromatography over silica gel (eluent: CH₂Cl₂/ethylacetate 80/20; 15-40 μm). Fraction 1 was crystallized from iPrOH. Theprecipitate was filtered off and dried. Yield: 1.3 g of4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile(E) (compound 1) (20%).

Example B1A

Compound 1 was Also Prepared as Follows

A mixture of 93.9 g (0.45 mol) of the hydrochloric acid salt ofintermediate 3, prepared according to Example A1c), and 109 g (0.4725mol) of intermediate 5 in 1.8 l of acetonitrile was prepared undernitrogen atmosphere. The mixture was stirred and refluxed for 69 hours,then allowed to cool to 55° C. The mixture was filtered and the residuewas washed with 200 ml of acetonitrile, followed by drying under reducedpressure at 50° C. overnight. 144.6 g (0.3666 mol) of the obtained solidwas brought in 1 l of K₂CO₃ 10% aqueous solution. The mixture wasstirred at room temperature followed by filtration. The obtained residuewas washed twice with water followed by drying at 50° C. under reducedpressure. The residue was brought in 6.55 l isopropanol and the mixturewas refluxed, then stirred overnight and filtered at room temperature.

The residue was dried at 50° C. under reduced pressure. Yield: 113.2 g(68.6%) of4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile(E) (compound 1).

Example B1B

Alternatively, compound 1 was also prepared as follows:

-   a) A mixture of intermediate 58 (0.00021 mol), prepared according to    Example A11, acrylonitrile (CH₂═CH—CN) (0.00213 mol), Pd(OAc)₂    (0.000043 mol), N,N-diethylethanamine (0.000043 mol) and    tris(2-methylphenyl)phosphine (0.00021 mol) in CH₃CN (7 ml) was    stirred in a sealed vessel at 150° C. overnight. H₂O was added. The    mixture was extracted with CH₂Cl₂. The organic layer was separated,    dried (MgSO₄), filtered and the solvent was evaporated. The residue    (0.15 g) was purified by column chromatography over silica gel    (eluent: CH₂Cl₂/ethyl acetate 80/20; 15-40 μm). Fraction 1 was    collected and the solvent was evaporated, yielding 0.045 g of    4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile    (E/Z=80/20). The solid was crystallized from diethylether. Yield:    0.035 g of    4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile (E)    (compound 1) (55%).-   b) 4.41 g (10 mmol) of intermediate 59 and 15 ml of    N,N-dimethylacetamide were brought in a 100 ml flask under nitrogen.    To this mixture were added 0.98 g of sodium acetate (12 mmol), 107    mg (0.1 mmol Pd) of Pd/C 10% (wet) and 1 ml (15 mmol) of    acrylonitrile. The mixture was heated at 140° C. and the evolution    of the reaction was followed by liquid chromatography. The reaction    yielded    4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile    (E/Z=80/20) which can be converted to    4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile (E)    as described above in Example B1Ba).

Example B2

a) The Preparation of Compound 2

A mixture of

(prepared according to A3.d-1) (0.0002 mol), 2-benzofuranylboronic acid(0.0005 mol), Pd(PPh₃)₄ (0.00002 mol) and Na₂CO₃ (0.0007 mol) in DME (3ml) was stirred and refluxed in a scelled tube for 3 hours. H₂O wasadded. The mixture was extracted with ethyl acetate. The organic layerwas separated, dried (MgSO₄), filtered and the solvent was evaporated.The residue (0.126 g) was purified by column chromatography over silicagel (eluent: CH₂Cl₂/CH₃OH 98/2; 15-40 μm). The pure fractions werecollected and the solvent was evaporated.

Yield: 0.011 g of compound 2 (10%).

b) The Preparation of Compound 3

A mixture of

(prepared according to A3.d-1) (0.0002 mol), tributyl-2-furanylstannane(0.0005 mol) and Pd(PPh₃)₄ (0.00001 mol) in dioxane (5 ml) was stirredat 80° C. The solvent was evaporated. The residue was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH 98/2; 15-40 μm).The pure fractions were collected and the solvent was evaporated. Theresidue (0.025 g) was crystallized from DIPE. The precipitate wasfiltered off and dried. Yield: 0.021 g of compound 3 (22%).c) The Preparation of Compound 104

A mixture of

(prepared according to A3.d) (0.005 mol),

[CAS 73183-34-3] (0.0055 mol), Pd(PPh₃)₄ (0.29 g) and K₂CO₃ (2.8 g, 0.02mol) in toluene (100 ml) and ethanol/water (5 to 10 ml) was stirred andrefluxed for a weekend. 5-Bromo-furan-2-carbaldehyde (0.0055 mol) andK₂CO₃ (1.4 g, 0.01 mol) were added. The mixture was stirred and refluxedovernight. The mixture (2.25 g) was purified by column chromatographyover silica gel (eluent: CH₂Cl₂/CH₃OH 100/0 to 99/1; 15-40 mm). The purefractions were collected and the solvent was evaporated. Yield: 0.135 gof compound 104 (6%).

Example B3

The Preparation of Compound 4

A mixture of intermediate 15 (see Table 1) (prepared according to A4.c)(0.0005 mol) and NaCN (0.0011 mol) in DMF (5 ml) was stirred at 80° C.overnight, poured out into H₂O and extracted with ethyl acetate. Theorganic layer was separated, dried (MgSO₄), filtered, and the solventwas evaporated. The residue (0.15 g) was purified by columnchromatography over kromasil (eluent: CH₂Cl₂/CH₃OH 99/1; 10 μm). Thepure fractions were collected and the solvent was evaporated. Theresidue (0.024 g) was purified by column chromatography over hypersil(eluent: acetonitrile/H₂O 52/48; 8 μm). The pure fractions werecollected and the solvent was evaporated. Yield: 0.02 g of compound 4(10%).

Example B4

a) The Preparation of Compound 50

A mixture of

(prepared according to A3.d) (0.0006 mol) and thiomorpholine (0.5 g) wasstirred at 120° C. for 48 hours, taken up in CH₂Cl₂ and the solvent wasevaporated. The residue (0.44 g) was purified by column chromatographyover kromasyl (eluent: CH₂Cl₂/CH₃OH 99/1; 10 μm). The pure fractionswere collected and the solvent was evaporated. Yield: 0.06 g (20%). Thisfraction was crystallized from diethyl ether/2-propanone. Theprecipitate was filtered off and dried. Yield: 0.035 g of compound 5.b) The Preparation of Compound 6

A mixture of intermediate 15 (see Table 1) (prepared according to A4.c)(0.000137 mol), N,N,N′-trimethyl-1,2-ethanediamine (2 equiv, 0.000275mol) and K₂CO₃ (2 equiv, 0.000275 mol) in CH₃CN (q.s.) was stirred at80° C. for 12 hours. H₂O was added. The mixture was extracted withCH₂Cl₂. The extract's solvent was evaporated. The residue was purifiedby chromatography. The product fractions were collected and the solventwas evaporated. Yield: 0.006 g of compound 6 (10.16%).

c) The Preparation of Compound 7

A mixture of intermediate 15 (see Table 1) (prepared according to A4.c)(0.0005 mol) in 3-hydroxy-propanenitrile (2 ml) was stirred overnight,poured out into H₂O and extracted with CH₂Cl₂. The organic layer wasseparated, dried (MgSO₄), filtered, and the solvent was evaporated. Theresidue was purified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH/NH₄OH 99/1/0.1; 15-40 μm). Two fractions (F1, F2) werecollected and the solvent was evaporated. Yield: 0.034 g F1 and 0.514 gF2. F2 was washed with HCl 3N and extracted with CH₂Cl₂. The organiclayer was separated, dried (MgSO₄), filtered, and the solvent wasevaporated. The residue was crystallized from DIPE. The precipitate wasfiltered off and dried. Yield: 0.039 g of compound 7 (18%)

d) The Preparation of Compound 105

A mixture of intermediate 50 (prepared according to A4c) (0.001 mol),KCN (0.0011 mol) and KI (0.00005 mol) in EtOH (15 ml) was stirred andrefluxed for 4 hours. The solvent was evaporated till dryness. Theresidue was taken up in CH₂Cl₂/H₂O. The mixture was extracted withCH₂Cl₂. The organic layer was separated, dried (MgSO₄), filtered, andthe solvent was evaporated. The residue (0.31 g) was purified by columnchromatography over kromasil (eluent: cyclohexane/EtOAc 70/30; 10 μm).Three fractions were collected and the solvent was evaporated. Yield:0.044 g of fraction 1, 0.11 g of fraction 2 and 0.055 g of fraction 3.Fraction 3 was crystallized from DIPE. The precipitate was filtered offand dried. Yield: 0.046 g of compound 105 (12%) (mp. 140° C.).

Example B5

a) The Preparation of Compound 8

A mixture of intermediate 9 (0.0001 mol) and hydroxylamine (0.0002 mol)in EtOH (7 ml) was stirred at room temperature for 3 hours, poured outinto K₂CO₃ 10% and extracted with CH₂Cl₂. The organic layer wasseparated, dried (MgSO₄), filtered and the solvent was evaporated. Theresidue (0.1 g) was crystallized from DIPE/CH₃CN. The precipitate wasfiltered off and dried. Yield: 0.026 g of compound 8.

b) The Preparation of Compound 9

A mixture of intermediate 9 (0.0002 mol) and O-methylhydroxylamine(0.0003 mol) in EtOH (10 ml) was stirred at room temperature overnight,poured out into H₂O and extracted with CH₂Cl₂. The organic layer wasseparated, dried (MgSO₄), filtered and the solvent was evaporated. Theresidue (0.13 g) was purified by column chromatography over kromasyl(eluent: cyclohexane/iPrOH/NH₄OH; 5 μm). The pure fractions werecollected and the solvent was evaporated. The residue (0.06 g) wascrystallized from DIPE. The precipitate was filtered off and dried.Yield: 0.036 g of compound 9 (34%).

Example B6

a) The Preparation of Compound 1 and 10

A mixture of (cyanomethyl)triphenylphosphonium chloride (0.0022 mol) andpotassium tert.-butoxide (0.0022 mol) in THF (7 ml) was stirred at 5° C.for 30 minutes under N₂ flow, then stirred at 5° C. for 30 minutes. Amixture of intermediate 13 (0.0015 mol) in THF (7 ml) was added. Themixture was stirred for 8 hours in darkness, poured out into H₂O andextracted with CH₂Cl₂. The organic layer was separated, dried (MgSO₄),filtered and the solvent was evaporated. The residue (1.4 g) waspurified by column chromatography over silica gel (eluent:toluene/iPrOH/NH₄OH 96/4/0.1; 15-40 μm). Two fractions (F1, F2) werecollected and the solvent was evaporated. Yield: 0.165 g of F1(E/Z=32/68) (30%) and 0.225 g of F2 (E/Z=90/10) (41%). F2 wascrystallized from CH₃CN/diethyl ether. Yield: 0.036 g of compound 1(7%). F1 was purified by column chromatography over kromasyl (eluent:toluene/iPrOH 98/2; 5 μm). The pure fractions were collected and thesolvent was evaporated. Yield: 0.029 g of compound 10 (5%).

b) The Preparation of Compound 11 (Z) and Compound 103 (E)

Potassium tert-terbutoxide (0.0196 mol) was added portionwise at 5° C.to a mixture of (1-cyanoethyl)-phosphonic acid diethyl ester (0.0196mol) in THF (25 ml) under N₂ flow. The mixture was stirred at 5° C. for30 minutes, then at room temperature for 30 minutes. A solution ofintermediate 13 (0.0130 mol) in THF (25 ml) was added. The mixture wasstirred at room temperature overnight, poured out into H₂O and extractedwith CH₂Cl₂. The organic layer was separated, dried (MgSO₄), filtered,and the solvent was evaporated. The residue (5.8 g) was purified bycolumn chromatography over silica gel (eluent: toluene/iPrOH/NH₄OH92/8/0.5; 15-40 μm). Four fractions (F1, F2, F3, F4) were collected andthe solvent was evaporated. Yield: 0.21 g of F1 (mixture Z/E=90/10),0.836 g of F2 (mixture Z/E=57/43), 0.9 g of F3 and 0.87 g of F4. F3 wascrystallized from DIPE/iPrOH to give 0.7 g of compound 11 (14%). F4 wascrystallized from DIPE/iPrOH to give 0.67 g of compound 103 (13%).

c) The Preparation of Compound 12 and 13

Potassium tert.-butoxide (0.0008 mol) was added portionwise at 5° C. toa mixture of (cyanomethyl)phosphonic acid diethyl ester (0.0005 mol) inTHF (20 ml) under N₂ flow. The mixture was stirred at room temperaturefor 30 minutes. A solution of

(prepared according to A3.d-1) (0.0005 mol) in THF (4 ml) was addeddropwise. The mixture was stirred at room temperature for 4 hours,poured out into H₂O and extracted with CH₂Cl₂. The organic layer wasseparated, dried (MgSO₄), filtered and the solvent was evaporated.Yield: 0.3 g. This fraction was purified by column chromatography overkromasil (eluent: CH₂Cl₂/CH₃OH 99/1; 5 μm). The pure fractions werecollected and the solvent was evaporated. Yield: 0.21 g.

This fraction was purified by column chromatography over kromasil(eluent: cyclohexane/ethyl acetate 50/50; 10 μm). Two fractions (F1, F2)were collected and the solvent was evaporated. Yield: 0.04 g of F1 and0.047 g F2. F1 was dried at 70° C. for 2 hours. Yield: 0.038 g ofcompound 13 (18%). F2 was dried at 70° C. for 2 hours. Yield: 0.041 g ofcompound 12 (20%).

d) The Preparation of Compound 14

Potassium tert.-butoxide (0.0013 mol) was added at 5° C. to a mixture of(cyanomethyl)phoshonic acid diethyl ester (0.0013 mol) in THF (10 ml)under N₂ flow. The mixture was stirred at 5° C. for 30 minutes. Amixture of

(prepared according to A3.d-1) (0.0009 mol) in THF (10 ml) was added.The mixture was stirred at room temperature for 4 hours, poured out intoH₂O and extracted with ethyl acetate. The organic layer was separated,dried (MgSO₄), filtered, and the solvent was evaporated. The residue(0.17 g) was purified by column chromatography over kromasil (eluent:CH₂Cl₂ 100 to CH₂Cl₂/CH₃OH 99/1; 5 μm). Two fractions (F1, F2) werecollected and the solvent was evaporated. Yield: 0.054 g F1 and 0.05 gF2. F1 was crystallized from DIPE/CH₃CN. The precipitate was filteredoff and dried. Yield: 0.046 g of compound 14 (12%).e) The Preparation of Compound 15

4-Fluorobenzeneacetonitrile (1.2 equiv, 0.000175 ml) was added to amixture of intermediate 13 (0.000146 mol) in CH₃OH (1 ml). NaOCH₃/CH₃OH(1.2 equiv, 0.000175 mol) was added at room temperature. The mixture wasstirred at 60° C. for 2 hours, then poured out into ice-water andextracted with CH₂Cl₂. The solvent was evaporated. The residue waspurified by chromatography. The product fractions were collected and thesolvent was evaporated. Yield: 0.009 g of compound 15 (13.42%).

f) The Preparation of Compound 106

A mixture of intermediate 13 (prepared according to A5.a) (0.0005 mol)and piperidine (0.0005 mol) in ethanol (5 ml) was stirred at roomtemperature for 30 minutes. 4,4-dimethyl-3-oxo-pentanenitrile (0.0011mol) was added. The mixture was stirred at room temperature overnight,poured out into H₂O and extracted with CH₂Cl₂. The organic layer wasseparated, dried (MgSO₄), filtered, and the solvent was evaporated. Theresidue (0.3 g) was purified by column chromatography over kromasil(eluent: CH₂Cl₂/CH₃OH 99/1; 10 μm). The pure fractions were collectedand the solvent was evaporated. The residue (0.2 g) was crystallizedfrom DIPE. The precipitate was filtered off and dried. Yield: 0.141 g ofcompound 106 (54%) (mp. 193° C.).

Example B7

The Preparation of Compound 16

A mixture of intermediate 14 (0.00005 mol) and carbonothioic dichloride(0.001 mol) in dioxane (10 ml) was stirred at room temperature. H₂O wasadded. The mixture was extracted with CH₂Cl₂. This fraction was purifiedby column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH90/10/0.1; 15-40 μm). The pure fractions were collected and the solventwas evaporated. Yield: 0.027 g of compound 16 (95.6%).

Example B8

The Preparation of Compound 17

The mixture of NaOCH₃ (0.001 mol) and2-(dimethylamino)-N-hydroxy-ethanimidamide (0.001 mol) in EtOH (10 ml)was stirred at room temperature for 30 minutes.

(prepared according to A3.d-1) (0.0005 mol) was added. The mixture wasstirred and refluxed overnight. H₂O was added. The mixture was extractedwith CH₂Cl₂. The residue was purified by column chromatography oversilica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 95/5/0.1; 15-40 μm). The purefractions were collected and the solvent was evaporated. Yield: 0.07 gof compound 17 (31%).

Example B9

The Preparation of Compound 18

nBuLi (0.0038 mol) was added dropwise at −70° C. to a mixture of iPr₂NH(0.0038 mol) in THF (5 ml) under N₂ flow. The mixture was brought to−20° C., stirred for 30 minutes and cooled again to −70° C. A solutionof CH₃CN (0.0038 mol) in THF (6 ml) was added dropwise. The mixture wasbrought to −20° C., stirred for 1 hour, cooled again to −70° C. Amixture of intermediate 13 (0.0009 mol) in THF (1 ml) was added. Themixture was stirred for 2 hours, poured out on ice at −30° C. andextracted with ethyl acetate. The organic layer was separated, dried(MgSO₄), filtered, and the solvent was evaporated. The residue (0.433 g)was purified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH 98/2; 35-70 μm). Two fractions were collected and thesolvent was evaporated. Yield: 0.056 g F1 and 0.23 g F2 (78%). F1 wascrystallized from DIPE/CH₃CN. The precipitate was filtered off anddried. Yield: 0.036 g of compound 18.

Example B9A

a) The Preparation of Compound 107

nBuLi[1.6] (0.0026 mol) was added dropwise at −70° C. to a mixture ofintermediate 13 (prepared according to A5.a) (0.0008 mol) in THF (10 ml)under N₂ flow. The mixture was stirred at −70° C. for 30 minutes. Asolution of (chloromethyl)triphenylphosphonium chloride (0.0026 mol) inTHF (5 ml) was added dropwise. The mixture was stirred at roomtemperature overnight, poured out into H₂O and extracted with EtOAc. Theorganic layer was separated, dried (MgSO₄), filtered and the solvent wasevaporated. The residue (0.7 g) was purified by column chromatographyover kromasil (eluent: CH₂Cl₂/CH₃OH 99/1; 10 μm). The pure fractionswere collected and the solvent was evaporated. The residue (0.155 g) waspurified by column chromatography over C18 (eluent: CH₃CN/NH₄Ac 0.5%60/40). The pure fractions were collected and the solvent wasevaporated. The residue (0.051 g) was crystallized from DIPE. Theprecipitate was filtered off and dried. Yield: 0.029 g of compound 107(9%). (mp. 250° C.)

b) The Preparation of Compound 108 and 109

nBuLi[1.6] (0.00261 mol) was added dropwise at −70° C. to a mixture of(chloromethyl)triphenylphosphonium chloride (0.00261 mol) in THF (10 ml)under N₂ flow. The mixture was stirred for 30 minutes. A solution ofintermediate 31 (prepared according to A4.a) (0.00087 mol) in THF (5 ml)was added dropwise. The mixture was stirred at room temperatureovernight, then poured out into H₂O and extracted with EtOAc. Theorganic layer was separated, dried (MgSO₄), filtered, and the solventwas evaporated. The residue (1.1 g) was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 98/2/0.1;15-40 μm). The pure fractions were collected and the solvent wasevaporated. The residue (0.3 g) was purified by column chromatographyover hypersil C18 (eluent: CH₃OH/NH₄Ac 0.5% 70/30). Two fractions (F1,F2) were collected and the solvent was evaporated. Yield: 0.097 g F1 and0.085 g F2. F1 was crystallized from DIPE. The precipitate was filteredoff and dried.

Yield: 0.045 g of compound 108 (14%) (mp. 165° C.). F2 was crystallizedfrom DIPE.

The precipitate was filtered off and dried. Yield: 0.049 g of compound109 (15%) (mp. 200° C.).

c) The Preparation of Compound 110

nBuLi[1.6] (1.1 ml, 0.0017 mol) was added dropwise at −70° C. to amixture of 1,1,1,3,3,3-hexamethyldisilazane (HN(TMS)₂)(0.0017 mol) inTHF (6 ml). The mixture was stirred at −70° C. for 30 minutes.Cyanofluoromethyl (0.0017 mol) was added. The mixture was stirred for 30minutes. Phosphorochloridic acid diethyl ester (0.0017 mol) was added.The mixture was stirred at −70° C. for 15 minutes. nBuLi[1.6] (1.1 ml,0.0017 mol) was added dropwise. The mixture was stirred for 30 minutes.A solution of intermediate 31 (prepared according to A4.a) (0.0008 mol)in THF (4 ml) was added. The mixture was stirred at room temperatureovernight, poured out into H₂O and extracted with CH₂Cl₂. The organiclayer was separated, dried (MgSO₄), filtered, and the solvent wasevaporated. The residue (0.5 g) was purified by column chromatographyover silica gel (eluent: CH₂Cl₂/EtOAc 95/5; 15-40 μm). Four fractions(F1, F2, F3, F4) were collected and the solvent was evaporated. Yield:0.026 g of compound 110 (8%) (mp. 254° C.).

d) The Preparation of Compound 111

A solution of (CuCl)₂ (0.00015 mol) in NH₃ aqueous (500 μl) was added toa mixture of intermediate 21 (prepared according to A5.b) (0.0014 mol)in DMSO (1 ml). A solution of CBr₄ (0.0044 mol) in DMSO (1.5 ml) wasadded at 0° C. The mixture was stirred at room temperature overnight,poured out on ice and filtered. The organic layer was washed withCH₂Cl₂, dried (MgSO₄), filtered and the solvent was evaporated. Theresidue (2.73 g) was purified by column chromatography over silica gel(eluent: CH₂Cl₂/CH₃OH 100/0 to 99/1; 15-40 μm). Two fractions werecollected and the solvent was evaporated. Yield: 0.007 g of fraction 1and 0.11 g of fraction 2. Fraction 2 was crystallized from DIPE. Theprecipitate was filtered off and dried. Yield: 0.075 g of compound III(mp. 223° C.).

Example B9B

a) The Preparation of Compound 112

A mixture of intermediate 23 (0.0005 mol), 1-hydroxybenzotriazole(0.0007 mol) and EDCI (0.0007 mol) in CH₂Cl₂ (10 ml) and THF (2 ml) wasstirred. A solution of NH(CH₃)₂. HCl (0.0006 mol) and Et₃N (0.0005 mol)was added. The mixture was stirred at room temperature for 12 hours. H₂Owas added. The mixture was extracted with CH₂Cl₂. The organic layer wasseparated, dried (MgSO₄), filtered, and the solvent was evaporated. Theresidue was purified by column chromatography over kromasil (eluent:CH₂Cl₂/CH₃OH 100/0 to 90/10; 5 μm). The pure fractions were collectedand the solvent was evaporated. Yield: 0.124 g (58%). This fraction waspurified by column chromatography over kromasil (eluent: CH₂Cl₂/CH₃OH99/1; 5 μm). The pure fractions were collected and the solvent wasevaporated. Yield: 0.045 g of compound 112 (21%) (mp.>264° C.).

b) The Preparation of Compound 113

A mixture of intermediate 57 (prepared according to A7.b) (0.0002 mol),1-hydroxybenzotriazole (0.0003 mol) and EDCI (0.0003 mol) in CH₂Cl₂ (10ml) was stirred. N-methyl-1-butanamine [CAS 110-68-9] (0.0002 mol) wasadded. The mixture was stirred at room temperature for 12 hours. H₂O wasadded. The mixture was extracted with CH₂Cl₂. The organic layer wasseparated, dried (MgSO₄), filtered, and the solvent was evaporated.Yield: 0.149 g. This fraction was purified by column chromatography overkromasil (eluent: CH₂Cl₂/CH₃OH 100/0 to 90/10; 5 μm). The pure fractionswere collected and the solvent was evaporated. Yield: 0.065 g. Thisfraction was taken up in DIPE. The precipitate was filtered off anddried. Yield: 0.035 g of compound 113 (30%) (mp. 212° C.).

c) The Preparation of Compound 114

A mixture of intermediate 23 (prepared according A7.a) (0.0005 mol),1-hydroxybenzotriazole (0.0007 mol) and EDCI (0.0007 mol) in CH₂Cl₂ (10ml) and THF (2 ml) was stirred. 3-(methylamino)propanenitrile (0.0006mol) was added. The mixture was stirred at room temperature for 12hours. H₂O was added. The mixture was extracted with CH₂Cl₂. The organiclayer was separated, dried (MgSO₄), filtered, and the solvent wasevaporated. The residue was purified by column chromatography overkromasil (eluent: CH₂Cl₂/CH₃OH 100/0 to 90/10; 5 μm). The pure fractionswere collected and the solvent was evaporated. Yield: 0.068 g. Thisfraction was crystallized from DIPE. The precipitate was filtered offand dried. Yield: 0.032 g of compound 114 (14%) (mp. 168° C.).

d) The Preparation of Compound 115

A mixture of

(0.000195 mol) and methylamine (2 equiv, 0.000390 mol) in THF (5 ml) andEt₃N (0.054 ml) was stirred at room temperature. EDCI (2 equiv, 0.000390mol) and 1-hydroxy-benzotriazole (2 equiv, 0.000390 mol) were added. Thereaction mixture was stirred at room temperature for 12 hours and takenup into H₂O. The organic layer was separated, dried, filtered and thesolvent evaporated. The product was isolated and purified by columnchromatography. Yield: 0.026 g of compound 115 (17.92%).

Example B9C

The Preparation of Compound 116

A mixture of intermediate 13 (prepared according to A5.a) (0.000291 mol)and isonicotinic acid hydrazide (2.5 equiv., 0.000728 mol) in ethanol (1ml) and CH₂Cl₂ (2 ml) was stirred and refluxed for 12 hours. The solventwas evaporated till dryness. The residue was purified by chromatography.Yield: 0.033 g of compound 116 (24.50%).

Example B9D

a) The Preparation of Compound 117

Sodium cyanoborohydride (0.0024 mol) was added at room temperature to asolution of intermediate 26 (prepared according to A9) (0.0008 mol) informaldehyde (0.5 ml) and CH₃CN (20 ml) under N₂ flow. Acetic acid (0.5ml) was added. The mixture was stirred at room temperature for 2 hours,poured out into H₂O/K₂CO₃ 10% and extracted with CH₂Cl₂. The organiclayer was separated, dried (MgSO₄), filtered, and the solvent wasevaporated. The residue (0.3 g) was purified by column chromatographyover hypersol (eluent: CH₂Cl₂/CH₃OH 97/3; 5 μm). The pure fractions werecollected and the solvent was evaporated. Yield: 0.08 g (28%). Thisfraction was crystallized from 2-propanone/diethyl ether. Theprecipitate was filtered off and dried. Yield: 0.012 g of compound 117(5%) (mp. 132° C.).

b) The Preparation of Compound 118

A mixture of

(prepared according to A9) (0.0015 mol) andtetrahydro-2,5-dimethoxyfuran (0.0077 mol) in acetic acid (10 ml) wasstirred and refluxed for 1 hour, then poured out into ice water andK₂CO₃ and extracted with CH₂Cl₂. The organic layer was separated, dried(MgSO₄), filtered, and the solvent was evaporated. The residue (1 g) waspurified by column chromatography over silica gel (eluent:cyclohexane/EtOAc 95/5; 15-40 μm). The pure fractions were collected andthe solvent was evaporated. Yield: 0.23 g. This fraction wascrystallized from DIPE/diethyl ether. The precipitate was filtered offand dried. Yield: 0.075 g. This fraction was crystallized again fromDIPE/diethyl ether. The precipitate was filtered off and dried. Yield:0.027 g of compound 118 (5%).

Example B9E

a) The Preparation of Compound 119

Tributylphoshine (0.0015 mol) was added to a mixture ofbut-2-enedinitrile (0.0015 mol) in THF (8 ml). The mixture was stirredand refluxed for 2 hours.

prepared according to A5.a) (0.0005 mol) was added. The mixture wasstirred and refluxed overnight. H₂O was added. The mixture was extractedwith CH₂Cl₂. The organic layer was separated, dried (MgSO₄), filteredand the solvent was evaporated. The residue (0.618 g) was purified bycolumn chromatography over kromasil (eluent: CH₂Cl₂ 100; 10 μm). Twofractions were collected and the solvent was evaporated. Yield: 0.03 gof compound 119 (13%).b) The Preparation of Compound 120

Intermediate 13 (prepared according to A5.a) (0.002 mol) was added to amixture of propanedinitrile (0.004 mol) and piperidine (0.004 mol) inethanol (10 ml). The mixture was stirred at room temperature for 5minutes. The solvent was evaporated. The residue was taken up in CH₂Cl₂and purified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH 98/2; 15-40 μm). The pure fractions were collected and thesolvent was evaporated. Yield: 0.6 g of compound 120.

Example B9F

The Preparation of Compound 122

nBuLi [1.6 M] (0.0016 mol) was added dropwise at −78° C. to a mixture ofintermediate 27 (prepared according to A10) (0.0004 mol) in THF (10 ml)under N₂ flow. The mixture was stirred at −78° C. for 1 hour, thenbrought to room temperature, stirred for 30 minutes and cooled to −78°C. A solution of 2-pyridinecarboxaldehyde (0.0004 mol) in THF (10 ml)was added. The mixture was stirred at room temperature for 2 hours,poured out on ice and extracted with EtOAc. The organic layer wasseparated, dried (MgSO₄), filtered, and the solvent was evaporated. Theresidue (0.32 g) was purified by column chromatography over silica gel(eluent: CH₂Cl₂/CH₃OH/NH₄OH 98/2/0.1; 10 μm). Two fractions werecollected and the solvent was evaporated. Yield: 0.021 g of compound 122(10.4%) (mp. 120° C.).

Example B10

The Preparation of Compound 20

NaBH₄ (0.0015 mol) was added portionwise at 5° C. to a mixture ofcompound 19 (see table 3) (prepared according to B1) (0.0014 mol) inCH₃OH (15 ml) under N₂ flow. The mixture was stirred at 5° C. for 1hour, poured out into H₂O and extracted with CH₂Cl₂. The organic layerwas separated, dried (MgSO₄), filtered, and the solvent was evaporated.The residue (0.15 g) was purified by column chromatography over silicagel (eluent: CH₂Cl₂/CH₃OH 99/1; 10 μm). The pure fractions werecollected and the solvent was evaporated. The residue (0.068 g, 12%) wascrystallized from DIPE. The precipitate was filtered off and dried.Yield: 0.032 g of compound 20.

Example B11

The Preparation of Compound 21

A mixture of compound 2 (see table 3) (0.0002 mol), 3-thienylboronicacid (0.0005 mol), Pd(PPh₃)₄ (0.00002 mol) and Na₂CO₃ (0.0007 mol) inDME (3 ml) was stirred and refluxed in a scelled tube for 3 hours. H₂Owas added. The mixture was extracted with ethyl acetate. The organiclayer was separated, dried (MgSO₄), filtered, and the solvent wasevaporated. The residue was purified by column chromatography oversilica gel (eluent: CH₂Cl₂/CH₃OH 98/2; 15-40 μm). The pure fractionswere collected and the solvent was evaporated. Yield: 0.04 g of compound21 (40%).

Example B12

The Preparation of Compound 23

A mixture of compound 22 (see table 3) (prepared according to B4.a)(0.0002 mol) and Raney Nickel (0.1 g) in CH₃OH (10 ml) was stirred atroom temperature for 15 minutes under a 2 bar pression of H₂, thenfiltered over celite. Celite was washed with CH₃OH. The filtrate wasevaporated. Yield: 0.48 g. This fraction was purified by columnchromatography over kromasyl (eluent: CH₂Cl₂/CH₃OH 99/1; 15-40 μm). Twofractions (F1, F2) were collected and the solvent was evaporated. Yield:0.13 g F1 and 0.13 g F2. F2 was crystallized from diethyl ether. Theprecipitate was filtered off and dried. Yield: 0.09 g of compound 23(20%).

Example B13

The Preparation of Compound 24

A mixture of compound 1 (0.0004 mol) and Pd/C (0.07 g) in CH₃OH (10 ml)was hydrogenated at room temperature for 5 hours under a 3 bar pressureof H₂, then filtered over celite, washed with CH₂Cl₂ and the solvent wasevaporated till dryness. The residue was crystallized from DIPE. Theprecipitate was filtered off and dried. The residue (0.7 g) was purifiedby column chromatography over kromasyl (eluent: CH₂Cl₂/CH₃OH 100/0 to99/1; 5 μm). The pure fractions were collected and the solvent wasevaporated. The residue (0.06 g) was crystallized from DIPE. Theprecipitate was filtered off and dried. Yield: 0.04 g of compound 24(27%).

Example B14

The Preparation of Compound 26

NaH 60% (0.0004 mol) was added at room temperature to a mixture ofcompound 25 (see Table 4) (prepared according to B6.c) (0.0004 mol) inTHF (30 ml). The mixture was stirred at room temperature for 1 hour. Asolution of ICH₃ (0.0004 mol) in THF (30 ml) was added. The mixture wasstirred at 60° C. for 2 hours, then cooled, poured out into H₂O andextracted with CH₂Cl₂. The organic layer was separated, dried (MgSO₄),filtered and the solvent was evaporated. The residue (0.12 g) waspurified by column chromatography over kromasil (eluent: CH₂Cl₂/CH₃OH99/1; 10 μm). The pure fractions were collected and the solvent wasevaporated. Yield: 0.049 g of compound 26 (32%).

Example B15

a) The Preparation of Compound 123

Jones's reagent (0.0056 mol) was added at 5° C. to a mixture of compound18 (prepared according to B9) (0.0029 mol) in 2-propanone (20 ml) underN₂ flow. The mixture was stirred at 5° C. for 2 hours, then poured outinto H₂O, basified with NaHCO₃ and extracted with CH₂Cl₂. The organiclayer was separated, dried (MgSO₄), filtered, and the solvent wasevaporated. The residue (1.5 g) was purified by column chromatographyover silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 98/2/0.1; 15-40 μm). Twofractions (F1, F2) were collected and the solvent was evaporated. Yield:0.122 g F1 (11%) and 0.19 g F2 (17%). F2 was crystallized from DIPE. Theprecipitate was filtered off and dried. Yield: 0.034 g of compound 123(mp. 150° C.).

b) The Preparation of Compound 124

A mixture of compound 123 (0.0005 mol) in POCl₃ (1.5 ml) was stirred at80° C. for 24 hours, poured out into ice and K₂CO₃ 10% and extractedwith CH₂Cl₂/CH₃OH. The organic layer was separated, dried (MgSO₄),filtered and the solvent was evaporated. The residue (0.14 g) waspurified by column chromatography over kromasil (eluent: CH₂Cl₂/CH₃OH99/1; 10 μm). The pure fractions were collected and the solvent wasevaporated. Yield: 0.026 g of compound 124.

Example B16

a) The Preparation of Compound 125

NaOH 5N (2 ml) was added dropwise at 50° C. to a mixture of compound 104(see Table 3) (prepared according to B2.c) (0.0003 mol) and NH₂OH, HCl(0.0004 mol) in ethanol (10 ml). The mixture was stirred at 50° C. for 2hours. Two-third of the mixture was evaporated. The mixture was pouredout into H₂O and extracted with CH₂Cl₂. The organic layer was washedwith K₂CO₃ 10%, dried (MgSO₄), filtered, and the solvent was evaporated.Yield: 0.21 g of compound 125.

b) The Preparation of Compound 126

1,1′-carbonyldiimidazole (0.0012 mol) was added to a mixture of compound125 (0.0003 mol) in THF (20 ml). The mixture was stirred and refluxedovernight, poured out into H₂O and extracted with CH₂Cl₂. The organiclayer was separated, dried (MgSO₄), filtered, and the solvent wasevaporated. The residue (0.17 g) was purified by column chromatographyover kromasil (eluent: CH₂Cl₂/CH₃OH 98/2; 10 μm). Two fractions werecollected and the solvent was evaporated. Yield: 0.035 g of fraction 1and 0.05 g of fraction 2. Both fractions were mixed and crystallizedfrom diethyl ether. The precipitate was filtered off and dried. Yield:0.05 g of compound 126 (38%) (mp. >260° C.).

Example B17

Preparation of Compound 253

-   a) 2.53 ml of acetonitrile, 0.056 g (0.253 mmol) of Pd(OAc)₂ and    0.154 g (0.506 mmol) of tris(2-methylphenyl)phosphine were brought    in a 100 ml flask under nitrogen and the mixture was stirred for 10    minutes. To the mixture was added 1 g (2.53 mmol) of intermediate    58, 0.51 ml (3.8 mmol) of N,N-diethylethanamine and 0.36 g (5.06    mmol) of acrylamide. The mixture was heated at reflux (80° C.) for 5    days yielding 28% of compound 253.-   b) In a 100 ml flask under N₂ were introduced 0.8 g (4.33 mmol; 1    eq.) of intermediate 3a (E), 1 g (4.33 mmom; 1 eq.) of intermediate    5 and 16 ml of 2-propanol. To this mixture 0.72 ml of HCl 6N in    2-propanol were added. The mixture was stirred under refluxed for 72    hours and then cooled yielding the hydrochloric acid salt of    compound 253, i.e. compound 254.

Compound 254 can be converted into the free base according to art-knownmethodologies (see also Example B1A).

Compound 253 can be converted into compound 1 according to the methoddescribed above in Example A1c)y).

The following Tables 3, 4 and 5 list compounds of formula (I) asprepared according to one of the above examples (Ex. No.).

TABLE 3

Physical data Comp Ex. mp. ° C./ No. No. R³ R⁴ (MH+)*  2 B2a2-benzofuranyl H mp. >240  21 B11 3-thienyl H mp. 220  3 B2b 2-furanyl Hmp. 228  28 B2a 2-thienyl H mp. 235  29 B2a phenyl H mp. 230  1 B1/B6a—CH═CH—CN h mp. 245, (E)  30 B2a 2,4-dichlorophenyl H (460)  31 B2a2-benzo[b]thienyl H (448)  32 B2a 1-naphthalenyl H (442)  33 B2a3-chlorophenyl H (426)  34 B2a 3-acetylphenyl H (434)  35 B2a3-methylphenyl H (406)  36 B2a 2-naphthalenyl H (442)  37 B2a4-chlorophenyl H (426)  38 B2a 4-methoxyphenyl H (422)  39 B2a4-methylthiophenyl H (438)  40 B2a

H  19 B1

H mp. 220  8 B5a —C(═N—OH)—CH(CH₃)₂ H mp. 156  20 B10

H mp. 205  27 B1

H mp. 193  41 B10

H mp. 200  42 B5a

H mp. 155  43 B4b

H mp. 110  44 B5b

H mp. 110  45 B5a —C(═N—OH)—CH₃ H mp. 135  9 B5b —C(═N—O—CH₃)—CH(CH₃)₂ Hmp. 185  46 B5b

H mp. 164  47 B4b —CH₂—N(CH₂—CH₃)₂ H mp. 150  48 B4b

H mp. 85  15 B6e

H (461)  49 B6e

H (449)  50 B6e

H (487)  51 B6e

H (493)  52 B6e

H (473)  53 B6e

H (443)  54 B6e

H (446)  55 B6e

H (449)  56 B6e

H (521)  57 B6e

H (457)  6 B4b —CH₂—N(CH₃)—CH₂—CH₂—N(CH₃)₂ H (430)  58 B4b

H (506)  59 B4b

H (428)  60 B4b

H (532)  61 B4b

H (504)  62 B4b

H (503)  63 B4b

H (472)  64 B4b

H (491)  65 B4b —CH₂—N(CH₃)—CH₂—CH₂—CH₂—CH₃ H (415)  66 B4b

H (442)  67 B4b

H (410)  68 B4b —CH₂—N(CH₃)—CH₂—CH₂—CH₃ H (401)  69 B4b

H (399)  70 B4b

H (396)  71 B4b —CH₂—N(CH₂—CH₂—O—CH₃)₂ H (461)  72 B4b

H (485)  73 B4b

H (456)  74 B4b

H (492)  75 B4b —CH₂—N(CH₃)—CH₂—CH₂—CN H (412)  76 B4b

H (443)  77 B4b

H (397)  78 B4b

H (417)  79 B4b

H (464)  80 B4b —CH₂—NH—CH₂—CH₂—N(CH₂—CH₃)₂ H mp, 105  81 B1

H mp. 240  82 B10

H mp. 170  24 B13 —CH₂—CH₂—CN H mp. 208  83 B8

H mp. >250° C.  14 B6d

H mp. 158  84 B6c —C(CH₃)═CH—CN H mp. 224° C.  18 B9 —CH(OH)—CH₂—CN Hmp. 252° C.  85 B4b

H (474)  86 B4b

H (473)  87 B4b

H (426)  88 B4b

H (424)  89 B4b

H (446)  90 B4b

H (397)  91 B4b

H (438)  92 B4b

H (438)  93 B4b

H (410)  94 B4b

H (410)  95 B4b

H (478)  96 B4b

H (473) 103 B6b —CH═C(CH₃)—CN H mp. 201° C. (E)  11 B6b —CH═C(CH₃)—CN Hmp. 246° C. (Z)  10 B6a —CH═CH—CN H mp. 258° C. (Z)  4 B3 —CH₂—CN H  17B8

H mp. 110° C.  97 B8

H mp. 240° C.  16 B7

H mp. >250° C.  7 B4c —CH₂—O—CH₂—CH₂—CN H mp >260  5 B4a4-thiomorpholinyl —NO₂ mp. 268  98 B4a 4-morpholinyl —NO₂ mp. 210  22B4a 1-piperidinyl —NO₂ mp. 252  23 B12 1-piperidinyl —NH₂ mp. 262  12B6c H —C(CH₃)═CH—CN (E) (381)  13 B6c H —C(CH₃)═CH—CN (Z) (381) 127 B1—N(CH₃)₂ H mp. 228° C. 123 B15a —C(═O)—CH₂—CN H mp. 150° C. 116 B9C

H (463) 128 B9C

H (480) 129 B9C

H (452) 130 B9C —CH═N—NH—C(═O)—CH₃ H (400) 131 B9C —CH═N—NH—C(═O)—CH₂—CNH (425) 132 B9C

H (468) 115 B9Bd —C(═O)—NH—CH₃ H (373) 134 B9Bd —C(═O)—N(CH₃)₂ H (387)135 B9Bd —C(═O)—N(CH₃)—CH₂—CH₃ H (401) 136 B9Bd —C(═O)—N(CH₂—CH₃)₂ H(415) 137 B9Bd —C(═O)—NH—CH₂—CH₃ H (387) 138 B9Bd —C(═O)—NH—CH₂—CN H(398) 139 B9Bd —C(═O)—N(CH₃)—CH₂—CN H (412) 140 B9Bd —C(═O)—NH—CH₂—C≡CHH (397) 141 B9Bd —C(═O)—NH—CH₂—CH═CH₂ H (399) 142 B9Bd—C(═O)—NH—CH(CH₃)₂ H (401) 143 B1 —N[CH₂—CH(CH₃)₂]₂ H mp. 238° C. 144B13 —CH₂—CH(CN)₂ H mp. 160° C. 106 B6f —CH═C(CN)—C(═O)—C(CH₃)₃ H (E),mp. 193° C. 145 B9f

H (E), mp. 229° C. 146 B9f

H (Z), mp. 258° C. 147 B9Ea —CH═C(CN)—CH₂—CN H (Z/E = 88/12) (406) 148B6c —C(CH₂—CH₃)═CH—CN H (E), mp. 173° C. 149 B6c —C(CH(CH₃)₂)═CH—CN H(E), mp. 132° C. 150 B6c —C(CH(CH₃)₂)═CH—CN H (Z), mp. 132° C. 151 B6b—CH═C(CH₃)—CN H (Z), mp. 246° C. 152 B6b —CH═C(CH₃)—CN H (E), mp. 201°C. 153 B13 —CH₂—CH(CH₃)—CN H mp. 187° C. 124 B15b —C(Cl)═CH—CN H 154B9Ba —CH═CH—C(═O)—N(CH₃)—CH₂—CN H (E) 112 B9Ba —CH═CH—C(═O)—N(CH₃)₂ H(E), mp. >264° C. 155 B9Bc

H (E), mp. 156° C. 156 B9Bc

H (E), mp. 168° C. 157 B9Bc

H (E), mp. >265° C. 158 B9Bc —CH═CH—C(═O)—N(CH₃)—CH₂—CH₃ H (E),mp. >260° C. 114 B9Bc —CH═CH—C(═O)—N(CH₃)—(CH₂)₂—CN H (E), mp. 168° C.159 B9Bc —CH═CH—C(═O)—N(CH₂—CH₃)₂ H (E), mp. 249° C. 160 B6b—C(CH₃)═C(CH₃)—CN H (E) 107 B9Aa —CH═CH—Cl H (Z), mp. 250° C. 161 B9Aa—CH═CH—Br H (Z), mp. 248° C. 111 B9Ad —CH═C(Br)₂ H mp. 223° C. 122 B9F

H (E), mp. 120° C. 162 B9F

H (E), mp. >260° C. 163 B9F

H mp. 128° C. 164 B9FF

H mp. 104° C. 125 B16a

H 104 B2c

H 165 B9F

H mp. 112° C. 166 B9F

H mp. 194° C. 167 B9F

H mp. 191° C. 126 B16b

H mp. >260° C. 168 B4c —CH₂—O—CH₂—CH₃ H mp. 201° C. 117 B9Da H —N(CH₃)₂mp. 132° C. 120 B9Eb —CH═C(CN)₂ H 253 B17a/b —CH═CH—C(═O)NH₂ H (E) 254B17b —CH═CH—C(═O)NH₂ H (E) HCl *(MH⁺) defines the mass of the protonatedcompound; it was determined with a MicroMass spectrometer equipped withan electrospray probe with a quadripolar analyser.

TABLE 4

Comp Ex. Physical data No. No. R³ R¹ mp. ° C./(MH+)*  25 B6c —CH═CH—CN Hmp. 256° C.  99 B3 —CH₂—CN H mp. 184° C. 100 B4b —CH₂—N(CH₂—CH₃)₂ H mp.172° C. 102 B13 —CH₂—CH₂—CN H mp. 224° C. 101 B4b —CH₂—N(CH₃)—CH₂—CH₂—CNH mp. 196° C.  26 B14 —CH═CH—CN CH₃ mp. 195° C. 169 B9Bd—C(═O)—N(CH₂—CH₃)₂ H mp. 172° C. 170 B4b —CH2—N(CH₃)—CH₂—CN H 171 B4b

H (398) 172 B2a

H mp. 158° C. 173 B4b —CH₂—N(CH₃)—CH₂—CH₂—N(CH₃)₂ H mp. 196° C. 174 B4b—CH₂—N(CH₃)—CH═N—CN H mp. 254° C. 175 B14 2-furanyl CH₃ mp. 178° C. 118B9Db

H 164° C. 176 B14

CH₃ mp. 188° C. 177 B9Aa —CH═CH—Br H (Z), mp. 169° C. 110 B9Ac—CH═C(F)—CN H (E), mp. 254° C. 178 B6b —CH═C(CH₃)—CN H (Z) 179 B6b—CH═C(CH₃)—CN H (E) 180 B9Bb

H (E) 181 B9Bc —CH═CH—C(═O)—NH-cyclopropyl H (E) (426) 182 B9Bc—CH═CH—C(═O)—NH—CH₂—CH₂—N(CH₃)₂ H (E) (427) 183 B9Bc—CH═CH—C(═O)—NH—CH₂—CH₂—CH₂—O—CH₃ H (E)(458) 184 B9Bc—CH═CH—C(═O)—NH—CH₂—CH(CH₃)₂ H (E)(442) 185 B9Bc—CH═CH—C(═O)—NH—CH₂—CH₂—CN H (E)439) 186 B9Bc

H (E)(468) 187 B9Bc —CH═CH—C(═O)—NH—CH₂—CH₂—CH₂—N(CH₃)₂ H (E)(471) 188B9Bc —CH═CH—C(═O)—NH—(CH₂)₃—O—CH₂—CH₃ H (E)(472) 189 B9Bc—CH═CH—C(═O)—NH—CH₂—CH₃ H (E)(414) 190 B9Bc—CH═CH—C(═O)—NH—CH₂—CH₂—O—CH₃ H (E)(444) 191 B9Bc—CH═CH—C(═O)—NH—CH(CH₃)₂ H (E)(428) 192 B4b

H (E)(491) 193 B4b

H (E)(444) 194 B4b —CH═CH—CH₂—N(CH₃)—CH₂—CH₂—CN H (E)(439) 195

H (E)(483) 196 B4b —CH═CH—CH₂—N(CH₂—CH₂—O—CH₃)₂ H (E)(488) 197 B4b

H (E)(476) 198 B4b —CH═CH—CH₂—N(CH₃)—CH₂—CH₂—CH₃ H (E)(428) 199 B4b—CH═CH—CH₂—N(CH₃)—CH₂—CH₂—N(CH₂—CH₃)₂ H (E)(485) 200 B4b—CH═CH—CH₂—N(CH₂—CH₃)—CH₃ H (E)(414) 201 B4b —CH═CH—CH₂—N(CH₂—CH₂—CH₃)₂H (E)(456) 202 B4b —CH═CH—CH₂—N(CH₃)—CH₂—CH₂—CH₂—CH₃ H (E)(442) 203 B4b

H (E)(438) 204 B4b

H (E)(442) 205 B4b

H (E)(455) 206 B4b —CH═CH—CH₂—N(benzyl)—CH₂—CH₂—N(CH₃)₂ H (E)(533) 207B4b —CH═CH—CH₂—N(CH₃)₂ H (E)(457) 208 B4b —CH═CH—CH₂—N(isopropyl)₂ H(E)(456) 121 B9Bb —CH═CH—C(═O)—NH₂ H (E) 209 B9Bb

H (E), mp. 116° C. 210 B9Bb

H (E), mp. 254° C. 211 B9Bb —CH═CH—C(═O)—N(CH₃)—CH₂—CH₂—OH H (E), mp.222° C. 212 B9Ba —CH═CH—C(═O)—N(CH₃)—CH₂—CN H (E), mp. 198° C. 213 B6c—C(CH₃)═CH—CN H (E) 214 B9Bc —CH═CH—C(═O)—N(CH₃)—CH₂—CH₂—CN H (E), mp.204° C. 215 B9Bc —CH═CH—C(═O)—N(CH₃)—CH₂—CH₂—CH₃ H (E), mp. 211° C. 216B9Bc

H (E), mp. 246° C. 217 B9Bc —CH═CH—C(═O)—N(CH₂—CH₃)₂ H (E), mp. 226° C.218 B9Bc

H (E), mp. 196° C. 219 B9Ba —CH═CH—C(═O)—N(CH₃)₂ H (E), mp. 225° C. 220B9E —CH═C(CN)—CH₂—CN H (Z), mp. 195° C. 109 B9Ab —CH═CH—Cl H (E), mp.200° C. 108 B9Ab —CH═CH—Cl H (Z), mp. 165° C. 221 B9Ba—CH═CH—C(═O)—NH—CH₃ H (E), mp. 260° C. 222 B9Bb—CH═CH—C(═O)—N(CH₂—CH₂—O—CH₃)₂ H (E), mp. 158° C. 223 B9Bb

H (E), mp. 208° C. 224 B9Bb

H (E), mp. 208° C. 113 B9Bb —CH═CH—C(═O)—N(CH₃)—CH₂—CH₂—CH₂—CH₃ H (E),mp. 212° C. 225 B4b —CH₂—N(CH₂—CH₂—CN)₂ H mp. 154° C. 226 B2a 2-furanylH mp. 162° C. *(MH⁺) defines the mass of the protonated compound; it wasdetermined with a MicroMass spectrometer equipped with an electrosprayprobe with a quadripolar analyser.

TABLE 5

Comp Ex. Physical data No. No. R³ R^(4a) R^(4b) X¹ mp. ° C. 227 B13—CH₂—CH₂—CN CH₃ H —NH mp. 186° C. 228 B4b —CH₂—N(CH₃)—CH₂—CN CH₃ H —NHmp. 138° C. 229 B6b —CH═C(CH₃)—CN CH₃ H —NH mp. 190° C. 230 B6c—CH═CH—CN CH₃ H —O— (E), mp. 254° C. 231 B6b —CH═C(CH₃)—CN CH₃ H —O— mp.150° C. 232 B6c —C(CH₃)═CH—CN CH₃ H —O— (E), mp. 234° C. 105 B4d—CH₂—O—CH₂—CH₃ CH₃ H —O— mp. 140° C. 233 B6b —CH═C(CH₃)—CN CH₃ Cl —NHmp. 214° C. 234 B13 —CH₂—CH₂—CN CH₃ H —O— mp. 199° C. 235 B13—CH(CH₃)—CH₂—CN CH₃ H —O— mp. 195° C. 236 B13 —CH₂—CH(CH₃)—CN CH₃ H —O—mp. 161° C. 237 B6c —CH═CH—CN CH₃ H —NH (E), mp. >264° C. 238 B3 —CH₂—CNCH₃ Cl —NH mp. 184° C. 239 B6c —CH═CH—CN CH₃ 2-furanyl —NH (E) mp. 175°C. 119 B9E —CH═C(CN)—CH₂—CN CH₃ 2-furanyl —NH 240 B9F

CH₃ Cl —NH mp. 248° C. Z/E = 50/50 241 B4b —CH₂—N(CH₃)—CH₂—CH₂—CN CH₃ Br—NH mp. 148° C. 242 B1 —CH═CH—CN H isopropyl —NH (E) 30%-(Z) 70% 243 B4b—CH₂—N(CH₃)—CH₂—CH₂—CN CH₃ Cl —NH mp. 85° C. 244 B6c —CH═CH—CN H Br —NH(E), mp. 270° C. 245 B6c —CH═CH—CN H —OCH₃ —NH (E), mp. 258° C. 246 B6b—C(CH₃)═C(CH₃)—CN CH₃ H —O— (E), mp. 214° C. 247 B6b —CH═C(CH₃)—CN CH₃Br —NH mp. 212° C. 248 B6c —CH═CH—CN CH₃ Br —NH (E), mp. 250° C. 249 B6b—CH═C(CH₃)—CN H —OCH₃ —NH mp. 166° C. 250 B6b —CH═C(CH₃)—CN H Br —NH mp.186° C. 251 B13 —CH₂—CH₂—CN H —OCH₃ —NH mp. 228° C. 252 B4c—CH₂—O—CH₂—CH₂—CN H Cl —NH mp. 168° C. 133 B6c —CH═CH—CN CH₃ Cl —NH (E),mp, 258° C.

C. Pharmacological Example

The pharmacological activity of the present compounds was examined usingthe following test.

A rapid, sensitive and automated assay procedure was used for the invitro evaluation of anti-HIV agents. An HIV-1 transformed T4-cell line,MT-4, which was previously shown (Koyanagi et al., Int. J. Cancer, 36,445-451, 1985) to be highly susceptible to and permissive for HIVinfection, served as the target cell line. Inhibition of the HIV-inducedcytopathic effect was used as the end point. The viability of both HIV-and mock-infected cells was assessed spectrophotometrically via the insitu reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT). The 50% cytotoxic concentration (CC₅₀ in M) was definedas the concentration of compound that reduced the absorbance of themock-infected control sample by 50%. The percent protection achieved bythe compound in HIV-infected cells was calculated by the followingformula:

${\frac{\left( {OD}_{T} \right)_{HIV} - \left( {OD}_{C} \right)_{HIV}}{\left( {OD}_{C} \right)_{MOCK} - \left( {OD}_{C} \right)_{HIV}}\mspace{14mu}{expressed}\mspace{14mu}{in}\mspace{14mu}\%},$whereby (OD_(T))_(HIV) is the optical density measured with a givenconcentration of the test compound in HIV-infected cells; (OD_(C))_(HIV)is the optical density measured for the control untreated HIV-infectedcells; (OD_(C))_(MOCK) is the optical density measured for the controluntreated mock-infected cells; all optical density values weredetermined at 540 nm. The dose achieving 50% protection according to theabove formula was defined as the 50% inhibitory concentration (IC₅₀ inM). The ratio of CC₅₀ to IC₅₀ was defined as the selectivity index (SI).

Table 6 lists the pIC₅₀ (−log IC₅₀), pCC₅₀ (−log CC₅₀) and pSI(pCC₅₀−pIC₅₀) values for the compounds of formula (I). For example, acompound with a IC₅₀ value of 10⁻⁹M, i.e. pIC₅₀=9, and a CC₅₀ value of10⁻⁵ M, i.e. pCC₅₀=5, has a SI of 10⁻⁵ M/10⁻⁹M=10.000, i.e. a pSI of5−9=−4.

TABLE 6 Co. No. pIC₅₀ (M) pCC₅₀ (M) pSI 21 8.4 4.9 −3.5 3 8.4 5.5 −2.9 19.4 5.0 −4.4 34 8.0 4.8 −3.2 19 8.4 4.8 −3.6 45 8.7 5.0 −3.8 49 8.0 4.8−3.2 70 8.1 4.8 −3.3 75 9.0 5.0 −4.0 78 8.4 4.9 −3.5 79 8.0 5.3 −2.7 849.0 4.5 −4.5 18 8.8 4.9 −4.0 25 9 4 −5 24 9.1 5.7 −3.4 81 9.1 5.6 −3.511 9.2 5.7 −3.5 10 9.2 6.3 −2.9 174 8.8 5.3 −3.5 227 9.5 <4.0 <−5.5 1448.6 6.4 −2.2 229 8.8 <4.0 <−4.8 118 8.4 4.1 <−4.1 177 8.3 <4.0 <−4.3 1067.7 5.2 −2.5 145 8.7 5.3 −3.4 147 9.4 5.7 −3.7 148 8.8 4.9 −3.9 230 9.2<4.0 <−5.2 231 9.2 <4.0 <−5.2 232 8.4 <4.0 <−4.4 105 7.2 <4.0 <−3.2 1108.6 4.3 −4.3 233 9.3 5.7 −3.6 234 8.7 <4.0 <−4.7 235 9.3 <4.0 <−5.3 2368.8 <4.0 <−4.8 149 9.1 5.3 −3.8 150 8.8 4.8 −4.0 237 8.9 <4.0 <−4.9 1519.1 5.5 −3.6 152 9.1 4.8 −4.3 178 8.8 5.7 −3.1 179 8.9 <4.0 <−4.9 1539.2 6.3 −2.9 124 8.5 4.7 −3.8 238 9.5 5.6 −3.9 112 9.1 4.9 −4.2 244 9.24 −5.2 209 8.6 4.9 −3.7 210 8.3 4.8 −3.5 155 8.8 6.3 −2.5 156 7.7 5.1−2.6 158 8 5.5 −2.5 212 9.1 5 −4.1 114 8.6 5.1 −3.5 213 9 4.8 −4.2 2148.6 5.1 −3.5 215 9.1 5.5 −3.6 216 8.2 5 3.6 219 9.1 5 −4.1 245 8.8 4−4.8 146 8.4 5.4 −3 247 9.2 6.2 −3 248 9.3 5.7 −3.5 249 8.5 4 −4.5 42 96.3 −2.7 251 8.9 5 −3.9 133 9.2 4 −5.2 9 8.8 4.8 −4 239 8.9 5 −3.9 2419.4 5.3 −4.1 126 8.4 4.9 −3.5

The invention claimed is:
 1. A combination containing (a) a compound offormula (I)

an N-oxide, a pharmaceutically acceptable addition salt, a quaternaryamine and a stereochemically isomeric form thereof, wherein-a¹=a²-a³=a⁴- represents a bivalent radical of formula:—CH═CH—CH═CH—  (a-1); -b¹=b²-b³=b⁴- represents a bivalent radical offormula:—CH═CH—CH═CH—  (b-1); n is 0, 1, 2, 3, 4, or 5; m is 1, 2, 3, or 4;R^(l) is selected from the group consisting of: hydrogen; aryl; formyl;C₁₋₆alkylcarbonyl; C₁₋₆alkyl; C₁₋₆alkyloxycarbonyl; C₁₋₆alkyl, whereinsaid C₁₋₆alkyl is substituted with a member selected from the groupconsisting of: formyl, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl, andC₁₋₆alkylcarbonyloxy; and C₁₋₆alkyloxyC₁₋₆alkylcarbonyl, wherein saidC₁₋₆alkyloxyC₁₋₆alkylcarbonyl is substituted with C₁₋₆alkyloxycarbonyl;each R² independently is selected from the group consisting of: hydroxy,halo, C₁₋₆alkyl optionally substituted with cyano or —C(═O)R⁶,C₃₋₇cycloalkyl, C₂₋₆alkenyl optionally substituted with one or morehalogen atoms or cyano, C₂₋₆alkynyl optionally substituted with one ormore halogen atoms or cyano, C₁₋₆alkyloxycarbonyl, carboxyl, cyano,nitro, amino, mono- or di(C₁₋₆alkyl)amino, polyhalomethyl,polyhalomethylthio, —S(═O)_(p)R⁶, —NH—S(═O)_(p)R⁶, —C(═O)R⁶, —NHC(═O)H,—C(═O)NHNH₂, —NHC(═O)R⁶,—C(═NH)R⁶ and a radical of formula

 wherein each A₁ independently is N, CH or CR⁶; and A₂ is NH, O, S orNR⁶; X₁ is selected from the group consisting of: —NR⁵—, —NH—NH—, —N═N—,—O—, —C(═O)—, C₁₋₄alkanediyl, —CHOH—, —S—, —S(═O)_(p)—,—X₂—C₁₋₄alkanediyl- and —C₁₋₄alkanediyl-X₂—; X₂ is selected from thegroup consisting of: —NR⁵—, —NH—NH—, —N═N—, —O—, —C(═O)—, —CHOH—, —S—,and —S(═O)_(p)—; R³ is R⁷; X₃ is selected from the group consisting of:—NR⁵—, —NH—NH—, —N═N—, —O—, —C(═O)—, —S—, —S(═O)_(p)—,—X₂—C₁₋₄alkanediyl-, —C₁₋₄alkanediyl-X_(2a)—,—C₁₋₄alkanediyl-X_(2b)—C₁₋₄alkanediyl, and —C(═N—OR⁸)—C₁₋₄alkanediyl-;with X_(2a) being selected from the group consisting of: —NH—NH—, —N═N—,—O—, —C(═O)—, —S—, and —S(═O)_(p)—; and with X_(2b) being selected fromthe group consisting of: —NH—NH—, —N═N—, —C(═O)—, —S—, and —S(═O)_(p)—;R⁴ is selected from the group consisting of: halo, hydroxy, C₁₋₆alkyl,C₃₋₇cycloalkyl, C₁₋₆alkyloxy, cyano, nitro, polyhaloC₁₋₆alkyl,polyhaloC₁₋₆alkyloxy, aminocarbonyl, C₁₋₆alkyloxycarbonyl,C₁₋₆alkylcarbonyl, formyl, amino, mono- or di(C₁₋₄alkyl)amino and R⁷; R⁵is selected from the group consisting of: hydrogen; aryl; formyl;C₁₋₆alkylcarbonyl; C₁₋₆alkyl; C₁₋₆alkyloxycarbonyl; C₁₋₆alkyl, whereinsaid C₁₋₆alkyl is substituted with a member selected from the groupconsisting of: formyl, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl andC₁₋₆alkylcarbonyloxy; and C₁₋₆alkyloxyC₁₋₆alkylcarbonyl, wherein saidC₁₋₆alkyloxyC₁₋₆alkylcarbonyl is substituted with C₁₋₆alkyloxycarbonyl;R⁶ is C₁₋₄alkyl, amino, mono- or di(C₁₋₄alkyl)amino orpolyhaloC₁₋₄alkyl; R⁷ is a monocyclic, bicyclic or tricyclic saturated,partially saturated or aromatic carbocycle or a monocyclic, bicyclic ortricyclic saturated, partially saturated or aromatic heterocycle,wherein each of said carbocyclic or heterocyclic ring systems mayoptionally be substituted with one, two, three, four or fivesubstituents each independently selected from the group consisting of:halo, hydroxy, mercapto, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl,mono or di(C₁₋₆alkyl)aminoC₁₋₆alkyl, formyl, C₁₋₆alkylcarbonyl,C₃₋₇cycloalkyl, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylthio,cyano, nitro, polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy, aminocarbonyl,—CH(═N—O—R⁸), R^(7a), —X₃—R^(7a) and R^(7a)—C₁₋₄alkyl; R^(7a) is amonocyclic, bicyclic or tricyclic saturated, partially saturated oraromatic carbocycle or a monocyclic, bicyclic or tricyclic saturated,partially saturated or aromatic heterocycle, wherein each of saidcarbocyclic or heterocyclic ring systems may optionally be substitutedwith one, two, three, four or five substituents each independentlyselected from the group consisting of: halo, hydroxy, mercapto,C₁₋₆alkyl, hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl, mono ordi(C₁₋₆alkyl)aminoC₁₋₆alkyl, formyl, C₁₋₆alkylcarbonyl, C₃₋₇cycloalkyl,C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylthio, cyano, nitro,polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy, aminocarbonyl, and—CH(═N—O—R⁸); R⁸ is selected from the group consisting of: hydrogen,C₁₋₄alkyl, aryl and arylC₁₋₄alkyl; p is 1 or 2; aryl is phenyl or phenylsubstituted with one, two, three, four or five substituents eachindependently selected from the group consisting of: halo, hydroxy,mercapto, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl, mono ordi(C₁₋₆alkyl)aminoC₁₋₆alkyl, C₁₋₆alkylcarbonyl, C₃₋₇cycloalkyl,C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylthio, cyano, nitro,polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy, aminocarbonyl, R⁷ and —X₃—R⁷;and (b) another antiretroviral compound.
 2. A pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and as activeingredients (a) a compound of formula (I)

an N-oxide, a pharmaceutically acceptable addition salt, a quaternaryamine and a stereochemically isomeric form thereof, wherein-a¹=a²-a³=a⁴- represents a bivalent radical of a formula:—CH═CH—CH═CH—  (a-1); -b¹=b²-b³=b⁴- represents a bivalent radical of aformula:—CH═CH—CH═CH—(b-1); n is 0, 1, 2, 3, or 5; m is 1, 2, 3, or 4; R¹ isselected from the group consisting of: hydrogen; aryl; formyl;C₁₋₆alkylcarbonyl; C₁₋₆alkyl; C₁₋₆alkyloxycarbonyl; C₁₋₆alkyl, whereinsaid C₁₋₆alkyl is substituted with a member selected from the groupconsisting of: formyl, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl, andC₁₋₆alkylcarbonyloxy; and C₁₋₆alkyloxyC₁₋₆alkylcarbonyl wherein saidC₁₋₆alkyloxyC₁₋₆alkylcarbonyl is substituted with C₁₋₆alkyloxycarbonyl;each R² independently is selected from the group consisting of: hydroxy,halo, C₁₋₆alkyl optionally substituted with cyano or —C(═O)R⁶,C₃₋₇cycloalkyl, C₂₋₆alkenyl optionally substituted with one or morehalogen atoms or cyano, C₂₋₆alkynyl optionally substituted with one ormore halogen atoms or cyano, C₁₋₆alkyloxycarbonyl, carboxyl, cyano,nitro, amino, mono- or di(C₁₋₆alkyl)amino, polyhalomethyl,polyhalomethylthio, —S(═O)_(p)R⁶, —NH—S(═O)_(p)R⁶, —C(═O)R⁶, —NHC(═O)H,—C(═O)NHNH₂, —NHC(═O)R⁶,—C(═NH)R⁶ and a radical of formula

 wherein each A₁ independently is N, CH or CR⁶; and A₂ is NH, O, S orNR⁶; X₁ is selected from the group consisting of: —NR⁵—, —NH—NH—, —N═N—,—O—, —C(═O)—, C₁₋₄alkanediyl, —CHOH—, —S—, —S(═O)_(p)—,—X₂—C₁₋₄alkanediyl- and —C₁₋₄alkanediyl-X₂—; X₂ is selected from thegroup consisting of: —NR⁵—, —NH—NH—, —N═N—, —O—, —C(═O)—, —CHOH—, —S—,and —S(═O)_(p)—; R³ is R⁷; X₃ is selected from the group consisting of:—NR⁵—, —NH—NH—, —N═N—, —O—, —C(═O)—, —S—, —S(═O)_(p)—,—X₂—C₁₋₄alkanediyl-, —C₁₋₄alkanediyl-X_(2a)—,—C₁₋₄alkanediyl-X_(2b)—C₁₋₄alkanediyl, and —C(═N—OR⁸)—C₁₋₄alkanediyl-;with X_(2a) being selected from the group consisting of: —NH—NH—, —N═N—,—O—, —C(═O)—, —S—, and —S(═O)_(p)—; and with X_(2b) being selected fromthe group consisting of: —NH—NH—, —N═N—, —C(═O)—, —S—, and —S(═O)_(p)—;R⁴ is selected from the group consisting of: halo, hydroxy, C₁₋₆alkyl,C₃₋₇cycloalkyl, C₁₋₆alkyloxy, cyano, nitro, polyhaloC₁₋₆alkyl,polyhaloC₁₋₆alkyloxy, aminocarbonyl, C₁₋₆alkyloxycarbonyl,C₁₋₆alkylcarbonyl, formyl, amino, mono- or di(C₁₋₄alkyl)amino and R⁷; R⁵is selected from the group consisting of: hydrogen; aryl; formyl;C₁₋₆alkylcarbonyl; C₁₋₆alkyl; C₁₋₆alkyloxycarbonyl; C₁₋₆alkyl, whereinsaid C₁₋₆alkyl is substituted with a member selected from the groupconsisting of: formyl, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl andC₁₋₆alkylcarbonyloxy; and C₁₋₆alkyloxyC₁₋₆alkylcarbonyl substituted withC₁₋₆alkyloxycarbonyl; R⁶ is C₁₋₄alkyl, amino, mono- ordi(C₁₋₄alkyl)amino or polyhaloC₁₋₄alkyl; R⁷ is a monocyclic, bicyclic ortricyclic saturated, partially saturated or aromatic carbocycle or amonocyclic, bicyclic or tricyclic saturated, partially saturated oraromatic heterocycle, wherein each of said carbocyclic or heterocyclicring systems may optionally be substituted with one, two, three, four orfive substituents each independently selected from the group consistingof: halo, hydroxy, mercapto, C₁₋₆alkyl, hydroxyC₁₋₆alkyl,aminoC₁₋₆alkyl, mono or di(C₁₋₆alkyl)aminoC₁₋₆alkyl, formyl,C₁₋₆alkylcarbonyl, C₃₋₇cycloalkyl, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl,C₁₋₆alkylthio, cyano, nitro, polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy,aminocarbonyl, —CH(═N—O—R⁸), R^(7a), —X₃—R^(7a) and R^(7a)—C₁₋₄alkyl;R^(7a) is a monocyclic, bicyclic or tricyclic saturated, partiallysaturated or aromatic carbocycle or a monocyclic, bicyclic or tricyclicsaturated, partially saturated or aromatic heterocycle, wherein each ofsaid carbocyclic or heterocyclic ring systems may optionally besubstituted with one, two, three, four or five substituents eachindependently selected from the group consisting of: halo, hydroxy,mercapto, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl, mono ordi(C₁₋₆alkyl)aminoC₁₋₆alkyl, formyl, C₁₋₆alkylcarbonyl, C₃₋₇cycloalkyl,C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylthio, cyano, nitro,polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy, aminocarbonyl, and—CH(═N—O—R⁸); R⁸ is selected from the group consisting of: hydrogen,C₁₋₄alkyl, aryl and arylC₁₋₄alkyl; p is 1 or 2; aryl is phenyl or phenylsubstituted with one, two, three, four or five substituents eachindependently selected from halo, hydroxy, mercapto, C₁₋₆alkyl,hydroxyC₁₋₆ alkyl, aminoC₁₋₆alkyl, mono or di(C₁₋₆alkyl)aminoC₁₋₆alkyl,C₁₋₆alkylcarbonyl, C₃₋₇cycloalkyl, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl,C₁₋₆alkylthio, cyano, nitro, polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy,aminocarbonyl, R⁷ or —X₃—R⁷; and (b) another antiretroviral compound. 3.A combination containing (a) a compound of formula (I′″)

an N-oxide, a pharmaceutically acceptable addition salt, a quaternaryamine and a stereochemically isomeric form thereof, wherein R¹, R², R³,R⁴, m and X₁ are as defined in claim 1; n′ is 0, 1, 2, 3 or 4; R^(2′) isselected from the group consisting of: halo, C₁₋₆alkyl, trihalomethyl,cyano, aminocarbonyl, and C₁₋₆alkyl substituted with cyano oraminocarbonyl; and (b) another antiretroviral compound.
 4. Thecombination as claimed in claim 3 wherein R^(2′) is cyano, aminocarbonylor C₁₋₆alkyl substituted with cyano or aminocarbonyl.
 5. Apharmaceutical composition comprising a pharmaceutically acceptablecarrier and as active ingredients (a) a compound of formula (I′″)

an N-oxide, a pharmaceutically acceptable addition salt, a quaternaryamine and a stereochemically isomeric form thereof, wherein R¹, R², R³,R⁴, m and X₁ are as defined in claim 2; n′ is 0, 1, 2, 3 or 4; R^(2′) isa member selected from the group consisting of: halo, C₁₋₆alkyl,trihalomethyl, cyano, aminocarbonyl, and C₁₋₆alkyl substituted withcyano or aminocarbonyl; and (b) another antiretroviral compound.
 6. Thecomposition as claimed in claim 5 wherein R^(2′) is cyano, aminocarbonylor C₁₋₆alkyl, wherein said C₁₋₆alkyl is substituted with cyano oraminocarbonyl.
 7. The combination as claimed in claim 1, comprising (a)a compound and an N-oxide, a pharmaceutically acceptable addition salt,a quaternary amine and a stereochemically isomeric form thereof,selected from the group consisting of:

and (b) another antiretroviral compound.
 8. The composition as claimedin claim 1, comprising a pharmaceutically acceptable carrier and asactive ingredients (a) a compound and an N-oxide, a pharmaceuticallyacceptable addition salt, a quaternary amine and a stereochemicallyisomeric form thereof, selected from the group consisting of:

and (b) another antiretroviral compound.